TWI778351B - A method of making a hydrogel coated contact lens - Google Patents

Abstract

Embodiments of the technology relate to a contact lens having a core that is covalently coated by a hydrogel layer, and to methods of making such a lens. In one aspect, embodiments provide for a coated contact lens comprising a lens core comprising an outer surface; and a hydrogel layer covalently attached to at least a portion of the outer surface, the hydrogel layer adapted to contact an ophthalmic surface, wherein the hydrogel layer comprises a hydrophilic polymer population having a first PEG species and a second PEG species, the first PEG species being at least partially cross-linked to the second PEG species.

Description

Method of making a hydrogel-coated contact lens Cross-Citation of Related Applications

This application claims priority to the U.S. Provisional Patent Applications of Havenstrite et al., including Application No. 61/693,689 filed on August 27, 2012, Application No. 61/800,835 filed on March 15, 2013, and Application No. 61/800,959 filed on March 15, 2013, each of which is titled "Multilayered Contact Lens," which are incorporated herein by reference in their entirety. This application also claims U.S. Provisional Patent Application No. 61/834813, filed June 13, 2013, by Havenstrite et al., entitled "Contact Lens with a Hydrophilic Layer" priority, which is incorporated by reference in its entirety.

incorporated by reference

All publications and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if individual publications or patent applications were expressly individually indicated to be incorporated by reference.

Specific examples of this technology relate to contact lenses with improved biocompatibility and wearability, and methods of making such improved lenses. More particularly, the technology relates to contact lenses having a layer of highly stable hydrogel overlying the core of the lens.

Contact lenses are medical devices that are placed in contact with the surface of the eye and are used for vision correction, cosmetic purposes, and the treatment of ocular lesions. Substances and materials can be deposited on the surface of contact lenses to improve the biocompatibility of the lenses, thus improving the interaction of the lenses with the area of the eye.

The current generation of contact lenses typically includes a core material containing polysiloxane. These lenses have many advantages over their rigid plastic predecessors. For example, silicone-containing lenses are biocompatible with the eye and have improved oxygen and fluid permeability for normal eye surface health. However, despite these advantages, a major challenge with silicone-containing lenses is the hydrophobicity of the silicone-containing materials, which can lead to abrasion and infection of eye tissue. Accordingly, the embodiments described herein provide contact lenses with improved hydrophilicity and biocompatibility, as well as practical and cost-effective methods of making such lenses.

Another challenge with current contact lens technology is the propensity for protein binding and absorption in the eye. For example, contact lenses can bind proteins to the lens to create protein deposits in the area of the eye. In addition, the lens can cause structural changes including protein denaturation, which can elicit an immune response , such as watering, red eyes, or swelling in the eye area. Accordingly, embodiments to be practiced provide contact lenses with improved resistance to unwanted protein interactions in the eye and methods of making such lenses.

Another consideration regarding the use of contact lenses is that some users experience discomfort similar to that of patients with dry eye. Dry eye is seen as the result of a rupture of the tear film covering the surface of the eye, or is particularly susceptible to such rupture. The tear film is arranged between the lower mucous layer secreted by the corneal cells and the upper lipid layer secreted by the meibomian glands on the conjunctival surface of the eyelid. The tear film includes an aqueous pool that spans the entire surface of the eye with a flow path that may at any time be independent of the lipid layer in which it is disposed.

The integrity of the tear film is important for critical functions such as oxygen and ion transport and lubrication of the ocular surface, which is in constant sliding contact with the eyelid. Dry eye may actually exist in the range where the tear film is vulnerable to rupture. In some cases, the patient may have a mild degree of dry eye that manifests when the integrity of the tear film is tested by the presence of contact lenses. To overcome this concern, some embodiments of the present invention provide contact lens technology that reduces or substantially eliminates tear film rupture from contact lenses.

It is understood that dry eye is considered herein as a non-limiting example for illustrative purposes. The methods and devices described can be used to treat or prevent other ocular pathologies including, but not limited to, glaucoma, corneal ulcers, scleritis, keratitis, iritis, and corneal vascular hyperplasia.

Some embodiments of the present invention provide a coated contact lens comprising a lens core comprising an outer surface, and a hydrogel layer covalently attached to at least a portion of the outer surface, the hydrogel layer adapted to contact the ocular surface, wherein the hydrogel layer comprises a hydrophilic polymer population having a first PEG species and a second PEG species, the first PEG species being at least partially cross-linked to the second PEG species.

In any of the foregoing embodiments, the hydrogel layer and core are covalently attached to the outer surface via a sulfonyl moiety. In any of the foregoing embodiments, the hydrogel layer and core are covalently attached to the outer surface via an alkylenesulfonyl moiety. In any of the foregoing embodiments, the hydrogel layer and core are covalently attached to the outer surface via a dialkenylsulfonyl moiety. In any of the foregoing embodiments, the hydrogel layer and core are covalently attached to the outer surface via an ethylsulfonyl moiety. In any of the foregoing embodiments, the hydrogel layer and core are covalently attached to the outer surface via a dipethenesulfonyl moiety.

In any of the foregoing embodiments, the hydrogel layer and core are covalently attached to the outer surface via thioether moieties. In any of the foregoing embodiments, the hydrogel layer and core are covalently attached to the outer surface via sulfonyl moieties and thioether moieties.

In any of the foregoing embodiments, the first PEG species comprises reactive sulfonyl groups and the second PEG species comprises reactive thiol groups, and the first PEG species and the second PEG species are via a thioether bond cross-linking.

In any of the foregoing embodiments, the hydrogel layer is substantially on the outer surface surrounding the core.

In any of the foregoing embodiments, the hydrogel layer and core are substantially optically clear. In any of the foregoing embodiments, the hydrogel layer is adapted to transmit light through the hydrogel layer to the ocular surface.

In any of the foregoing embodiments, the hydrogel layer comprises a thickness between about 50 nm and about 500 nm. In any of the foregoing embodiments, the hydrogel layer comprises a thickness of less than about 100 nm. In any of the foregoing embodiments, the hydrogel layer comprises a maximum thickness of about 10 microns.

In any of the foregoing embodiments, the first portion of the hydrogel layer includes a first thickness that is different from the second thickness of the second portion of the hydrogel layer.

In any of the foregoing embodiments, the first and second PEG species are branched species having a branching number between 2 and 12 branching arms.

In any of the preceding embodiments, wherein the first PEG species comprises a reactive electron pair accepting group, and the second PEG species comprises a reactive nucleophile, the reactive electron pair accepting group and the reactivity Nucleophilic groups are suitable for reaction to form crosslinks between the first PEG species and the second PEG species. In any of the foregoing embodiments, the reactive electron pair accepting group is a moiety. In any of the foregoing embodiments, the reactive nucleophilic group is a thiol moiety.

In any of the foregoing embodiments, the reactive electron pair accepting group of the first PEG species is covalently bonded to the outer surface of the core.

In any of the foregoing embodiments, the coated lens includes an advancing contact angle of between about 20 degrees and about 50 degrees. In some embodiments, the advancing contact angle is between about 25 degrees to about 35 degrees.

In any of the foregoing embodiments, the hydrogel layer comprises between 80% and about 98% by weight water.

In any of the foregoing embodiments, the core consists of polysiloxane. In any of the foregoing embodiments, the core comprises polysiloxane. In any of the foregoing embodiments, the core is substantially free of polysiloxane. In any of the foregoing embodiments, the core comprises a hydrogel.

Another aspect of the invention relates to a multilayer contact lens comprising a lens core layer covered by an outer hydrophilic PEG polymer layer, wherein the hydrophilic polymer layer comprises a first PEG macromonomer subpopulation having electron pair accepting moieties and A second PEG macromonomer subpopulation having a first nucleophilic reactive moiety, wherein the first and second PEG macromonomer subpopulations are systemically cross-linked.

In any of the foregoing embodiments, the hydrophilic polymer layer is formed by covalent bonding between an electron pair accepting moiety of the first PEG macromonomer and a second nucleophilic reactive moiety on the surface of the core layer is attached to the core layer by bonding. In any of the foregoing embodiments, the covalent linkage between the core layer and the electron pair accepting moiety is a thioether moiety. In any of the foregoing embodiments, the concentration of the electron pair accepting moiety is about 1% to about 30% higher than the concentration of the first nucleophilic reactive moiety. In any of the foregoing embodiments, the concentration of the electron pair accepting moiety is about 5% to about 20% higher than the concentration of the first nucleophilic reactive moiety.

In any of the foregoing embodiments, the electron pair accepting moiety is sulfonyl. In any of the foregoing embodiments, the first nucleophilic reactive moiety is a thiol group.

In any of the foregoing embodiments, the hydrophilic polymer layer comprises one or more branched PEG polymer species. In any of the foregoing embodiments, the branched PEG polymer species comprises a branching number between about 2 and about 12 arms. In any of the foregoing embodiments, the branched PEG polymer species comprises star-shaped branches.

In any of the foregoing embodiments, the first and second PEG macromonomers each have a molecular weight between about 1 kDa and about 40 kDa. In any of the foregoing embodiments, the molecular weight is between about 5 kDa and about 30 kDa.

In any of the foregoing embodiments, the hydrophilic PEG layer comprises between 80% and about 98% by weight water. In any of the foregoing embodiments, the hydrophilic PEG layer comprises between 85% and about 95% by weight water.

In any of the foregoing embodiments, the hydrophilic PEG layer has a thickness of less than about 1 micron. In any of the foregoing embodiments, the hydrophilic PEG layer has a thickness of less than about 5 microns. In any of the foregoing embodiments, the hydrophilic PEG layer has a maximum thickness of about 10 microns. In any of the foregoing embodiments, the hydrophilic PEG layer has a maximum thickness of between about 1 micron and about 5 microns. In any of the foregoing embodiments, the hydrophilic PEG layer has a thickness between about 50 nm and about 500 nm. In any of the foregoing embodiments, the hydrophilic PEG layer Has a thickness between about 100 nm to about 250 nm.

In any of the preceding embodiments, the hydrophilic PEG layer further comprises at least one active agent. In any of the foregoing embodiments, the at least one active agent is selected from the group consisting of UV absorbers, visibility colorants, antimicrobial agents, bioactive agents, leachable lubricants, leachable tear stabilizers or any mixture thereof.

Another aspect of the present invention pertains to a method of making a PEG hydrogel-coated contact lens comprising the steps of: reacting the outer surface of the contact lens with a first PEG species of a hydrophilic polymer solution, wherein the first PEG a species comprising an electron pair accepting moiety, and a first portion of the electron pair accepting moiety forms a covalent attachment to the outer surface of the contact lens via a first nucleophilic conjugation reaction; and causing the first portion of the hydrophilic polymer solution The PEG species is reacted with a second PEG species of the hydrophilic polymer solution, the second PEG species comprising a second moiety suitable for being covalent with the electron pair accepting moiety of the first PEG species in a second nucleophilic conjugation reaction linked to at least partially cross-link the nucleophilic reactive moieties of the first and second PEG species, wherein the PEG hydrogel coating is formed and attached to the stealth by the first and second nucleophilic covalent reactions The outer surface of the glasses.

In any of the foregoing embodiments, it further comprises the step of modifying the outer surface of the contact lens to form a plurality of reactive nucleophilic sites on the outer surface. In any of the foregoing embodiments, the modifying step includes exposing the outer surface of the contact lens to a gas plasma treatment.

In any of the preceding embodiments, the step of reacting the outer surface of the contact lens with the first PEG species comprises reacting at least a portion of A plurality of reactive nucleophilic sites on the outer surface react with a first moiety of electron pair accepting moieties on the first PEG species.

In any of the foregoing embodiments, both the first and second nucleophilic covalent reactions are 1,4-nucleophilic addition reactions.

In any of the foregoing embodiments, the first and second nucleophilic covalent reactions are both Michael-type reactions.

In any of the foregoing embodiments, both the first and second nucleophilic covalent reactions are click reactions.

In any of the foregoing embodiments, the nucleophilic reactive moiety of the second PEG species is a thiol group, and the electron pair accepting moiety of the first PEG species is a thiol group.

In any of the foregoing embodiments, the first PEG species and the second PEG species are cross-linked via thioether moieties.

In any of the foregoing embodiments, the hydrophilic polymer solution comprises substantially equal concentrations of the first and second PEG species.

In any of the foregoing embodiments, the concentration of electron pair accepting moieties of the first PEG species is about 1% to about 30% higher than the concentration of nucleophilic reactive moieties of the second PEG species. In any of the foregoing embodiments, the concentration of electron pair accepting moieties of the first PEG species is about 5% and about 20% higher than the concentration of nucleophilic PEG reactive moieties of the second PEG species.

In any of the foregoing embodiments, the reaction steps are performed at a temperature between about 15°C and about 100°C. In any of the foregoing embodiments, the reaction steps are performed at a temperature between about 20°C and about 40°C. In any of the foregoing embodiments, the reaction steps The system is run at a pH between about 7 and about 11.

In any of the foregoing embodiments, the contact lens includes a core that is substantially free of polysiloxane and includes a hydrogel core.

In an exemplary embodiment, the present invention is a contact lens comprising: a polysiloxane-containing layer and a first polyethylene glycol-containing layer; wherein the contact lens has a layered structure; the first polyethylene glycol-containing layer is Subunits of the polymer are substantially all polyethylene glycol subunits; and the first polyethylene glycol-containing layer and the polysiloxane-containing layer are covalently attached.

In an exemplary embodiment, according to the preceding paragraph, a second polyethylene glycol-containing layer is additionally included; wherein the subunits of the polymer of the second polyethylene glycol-containing layer are substantially all polyethylene glycol subunits; Two polyethylene glycol-containing layers and the polysiloxane-containing layer are covalently attached.

In an exemplary embodiment, according to any of the preceding paragraphs, the contact lens includes an anterior surface and a posterior surface, and wherein the layered structural construct is that the anterior surface is a first polyethylene glycol-containing layer and the posterior surface is a poly A silicon oxide layer, or the front surface is a polysiloxane-containing layer and the rear surface is a first polyethylene glycol-containing layer.

In an exemplary embodiment, according to any of the preceding paragraphs, the contact lens includes an anterior surface and a posterior surface, and wherein the layered structural configuration is that the anterior surface is a first polyethylene glycol-containing layer and the posterior surface is a second Contains polyethylene glycol layer.

In an exemplary embodiment, according to any of the preceding paragraphs, the present invention additionally includes an inner layer, wherein the polysiloxane-containing layer is the inner layer.

In an exemplary embodiment, according to any of the preceding paragraphs , the contact lens has a contact angle between about 10 degrees to about 20 degrees.

In an exemplary embodiment, according to any of the preceding paragraphs, the first polyethylene glycol-containing layer is substantially non-swellable.

In an exemplary embodiment, according to any of the preceding paragraphs, the first polyethylene glycol-containing layer is substantially non-swellable and the second polyethylene glycol-containing layer is substantially non-swellable.

In an exemplary embodiment, according to any of the preceding paragraphs, the thickness of the polysiloxane-containing layer is substantially uniform, and the thickness of the first polyethylene glycol-containing layer is substantially uniform.

In an exemplary embodiment, according to any of the preceding paragraphs, the thickness of the second polyethylene glycol layer is substantially uniform, and the front polyethylene glycol layer and the rear polyethylene glycol layer merge at the perimeter of the contact lens to completely seal The polysiloxane-containing layer.

In an exemplary embodiment, according to any of the preceding paragraphs, the polysilicon-containing layer has an average thickness of between about 1 micrometer and about 100 micrometers.

In an exemplary embodiment, according to any of the preceding paragraphs, the polysilicon-containing layer has an average thickness between about 25 microns and about 75 microns.

In an exemplary embodiment, according to any of the preceding paragraphs, the first polyethylene glycol layer has an average thickness of between about 10 microns and about 25 microns.

In an exemplary embodiment, according to any of the preceding paragraphs, the second polyethylene glycol layer has between about 1 micron and about 40 microns average thickness.

In an exemplary embodiment, according to any of the preceding paragraphs, the second polyethylene glycol layer has an average thickness between about 10 microns and about 25 microns.

In an exemplary embodiment, according to any of the preceding paragraphs, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a sulfonyl moiety.

In an exemplary embodiment, according to any of the preceding paragraphs, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a sulfonyl moiety.

In an exemplary embodiment, according to any of the preceding paragraphs, the polysiloxane-containing layer is at least 99% by weight polysiloxane.

In an exemplary embodiment, according to any of the preceding paragraphs, the polysiloxane-containing layer is at least 80 wt% _H2O .

In an exemplary embodiment, the polysilicon-containing layer is lotrafilcon or balafilcon or NuSil Med 6755 according to any of the preceding paragraphs.

In an exemplary embodiment, according to any of the preceding paragraphs, UV absorbers, visibility colorants, antimicrobial agents, bioactive agents, leachable lubricants, leachable tear stabilizers, and mixtures thereof are additionally included.

In an exemplary embodiment, according to any of the preceding paragraphs, the UV absorber, visibility colorant, antimicrobial agent, bioactive agent, leachable lubricant, or leachable tear stabilizer is in a polysiloxane-containing layer. middle.

In an exemplary embodiment, the present invention is a lens kit comprising a contact lens according to any of the preceding paragraphs, and a packaging solution.

In an exemplary embodiment, according to the preceding paragraph, the packaging solution comprises a viscosity enhancing polymer, polyethylene glycol, a mucoid material or a surfactant.

In an exemplary embodiment, the present invention is a method of making a contact lens according to any of the preceding paragraphs.

Exemplary embodiments of this technology relate to having a matrix, core or host material and a hydrophilic layer attached to the surface of the body/core/matrix. In some embodiments, the core or matrix is a polysiloxane-containing material, such as a polysiloxane core or a polysiloxane material. In some embodiments, the core or matrix may contain only polysiloxane-containing materials. In some embodiments, the core/host/matrix is composed of a polysiloxane-containing material. In other instances, the core or matrix includes from about 10% to about 20% polysiloxane-containing material. In other variations, the core/body/matrix may contain about 100% polysiloxane. In other embodiments, the contact lens substrate may contain polysiloxane, hydrogel, and water. In other embodiments, the contact lens can be made of any material, not limited to polysiloxane-containing materials.

In other specific examples, the hydrophilic layer may be formed of a hydrophilic polymer. In some variations, the hydrophilic layer is a hydrogel that includes one or more polymer networks. In some variations, the hydrogel polymer network is cross-linked. In other examples, the hydrogel is a cross-linked polyethylene glycol (PEG) network.

In another embodiment, the contact lens core is chemically bonded to the hydrophilic layer. For example, in some embodiments, the hydrogel layer is covalently bonded to the surface of the core. In other variations, the covalent linkage occurs between reactive groups in a click reaction. In some embodiments, the reactive groups are selected based on the desired thermodynamic driving force in the reaction formed. In some cases, one or more moieties of the matrix or core are attached to the hydrophilic layer.

Other variations provide a contact lens with a layer of a cross-linked hydrophilic polymer (eg, polyethylene glycol) on portions of the contact lens surface to improve the hydrophilicity of the contact lens surface (in some embodiments, as an advancing contact). angle reduction) and enhanced contact lens ocular region interaction. Some device or structure specific examples relate to the hydrophilic polymer itself, not specifically including the underlying lens core.

Other embodiments provide methods of forming contact lenses having a hydrophobic core with a hydrophilic layer. In some variations, the method includes the steps of depositing a cross-linked hydrophilic polymer onto the surface of the contact lens, and covalently attaching the cross-linked hydrophilic polymer to the contact lens surface. Other variations can include activating the lens surface and incubating the lens in a low concentration branched hydrophilic polymer solution. In some embodiments, the branched hydrophilic polymer includes reactive functional groups that are reactive with each other and with the lens surface.

In some embodiments, the method includes forming a substantially optically clear, crosslinked hydrophilic polymer on the contact lens. In some cases, the optical film improvement can be an underlying layer of polysiloxane-containing contact lens material Wetability of contact lenses.

2/10/404a/404b: Contact Lenses

4/12/62: Concave Surface

6/14/64: Convex Surface

8: perimeter or perimeter

16: Tear film

18/60/210/500: Lens core

20: Hydrophilic polymer layer

40: Eyes

42: Eyelid

44: Surface of the inner conjunctiva

46: glasses

48: Corneal Surface

50: Iris

51: First branch polymer species

52: Second branch polymer species

54/61/63: Covalent Bonding

70A: First hydrophilic polymer layer

70B: Second hydrophilic polymer layer

N1/N2: Reaction part

P1: first polymer species

P2: Dipolymer species

N: reactive functional group

A: Reactive functional group

B: reactive group

100: Settings

102: Lens holding fixture

104: Test Lenses

106: Bubbles

108: Syringe Pump

160: Lenses in Non-Reactive Positions

162: reactive position

200: Schematic

202: Nucleophilic part

204: Electronic Pair Acceptance Section

206:PEG-thiol

214/216: Conjugation Reactions

400: Continuously stirred reaction tank

402: Agitator

404: Feed line or conduit

406: Reaction solution input or inflow

408: Outlet or outflow opening or conduit

501: Convex side

502: Non-mixed solution

503: Concave side

504: UV light

506: Vacuum suction cup

The novel features of the present invention are set forth with particularity in the scope of the subsequent patent application. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description, which illustrates specific examples utilizing illustrations of the principles of the invention.

Figure 1A shows a contact lens with concave and convex surfaces.

IB is a cross-sectional view of an example contact lens with a covalently attached, cross-linked hydrogel layer.

FIG. 2 is a cross-sectional view of the contact lens shown in FIG. 1B on the cornea.

Figures 3A-3B show a first polymer species and a second polymer species with individual reactive groups A and N.

4A-4B show the reaction between a sulfonyl group and a thiol group.

Figures 5A-5C show schematic representations of hydrophilic polymers with two species covalently attached to the lens core.

6A-6C show trapped bubble tests.

Figure 7 shows the activated lens surface.

8 is a schematic diagram of first and second reactions with primary reactants.

Figures 9A-9D show more detailed details of the reactants and reactions described in Figure 8 .

10A-10B are flowcharts of the exemplary method described.

11A-11B show schematic diagrams of a continuous stirred tank reactor.

12A-12B show a method of making a lens with two side hydrogel layers of different depths or compositions.

13A-13T show the contact angles of example lenses.

14A-14J show the MATLAB code for the contact angle calculation.

As shown in FIG. 1A , the contact lens 2 can be understood as a body having a concave surface 4 and a convex surface 6 . The lens body may include a perimeter or perimeter 8 between the surfaces. The peripheral edge may also include a peripheral edge between the surfaces.

The concave surface 4 can also be referred to as a rear surface, and the convex surface 6 can also be referred to as a front surface, which is a term used for the specific position when the user wears it. In practice, the concave surface of the lens is adapted to be worn against or adjacent to the surface of the eye. When worn, the concave surface rests on the user's corneal surface 48 (see Figure 2). The convex surface faces outward and is exposed to the environment when the eye 40 is open. When the eye 40 is closed, this convex surface is located adjacent to or resting on the inner conjunctival surface 44 of the eyelid 42 (see Figure 2).

Since the convex and concave surfaces of the lens may be placed on or adjacent to eye tissue, such as the corneal surface, the properties of these surfaces can greatly affect user comfort and wear as described above. For example, the lens may rupture the tear film 16 of the eye 40, causing symptoms associated with dry eye. As such, embodiments described herein provide for applying a hydrophilic polymer layer on at least one of the lens surfaces to improve the wettability and wearability of the lens with minimal tearing Coated contact lenses with ruptured membranes.

In one embodiment, a coated contact lens to be practiced includes a core or body material having at least one surface having a hydrophilic polymer layer. In some cases, the hydrophilic layer is suitable for placement against the surface of the eye. The hydrophilic layer may cover a portion of the lens core surface. Alternatively, the hydrophilic layer may completely or substantially completely cover the core surface.

In other variations, more than one core surface has a hydrophilic layer. For example, both the concave and convex surfaces of the lens are coated with a hydrophilic polymer layer. Each hydrophilic layer on one of the concave or convex surfaces can independently fully or partially cover the respective surface. In some cases, the layers on each side of the core form a contiguous hydrophilic layer across the entire surface of both.

In other variations, the hydrophilic polymer layer is formed from a network of cross-linked hydrogel polymers having one or more cross-linked species. The hydrophilic polymer network may be partially cross-linked or substantially fully cross-linked. In some variations, the hydrophilic polymer is crosslinked to about 95% end group conversion.

Referring to Figure IB, a cross-section of an exemplary embodiment of a coated contact lens 10 is shown. Coated contact lens 10 includes a lens core 18 and a hydrophilic polymer layer 20 attached to the core 18 . As shown, a hydrophilic polymer layer 20 surrounds the core 18 . Both the concave and convex surfaces 12 , 14 are coated with the same hydrophilic polymer layer 20 which extends to the periphery 8 of the core 10 on both sides of the lens 18 . As shown, the outer hydrophilic layer 20 extends over substantially the entire circumferential edge portion 18 .

Referring to FIG. 2, the coated contact lens 10 of FIG. 1B is positioned on the eye 40 of a user. The eye 40 is shown with glasses 46 and an iris 50 . The concave surface 12 of the lens 10 is configured and centered on the cornea. The convex surface 14 of the lens 10 faces outward, facing the environment when the eye 40 is open. The convex surface 14 is adjacent to the interior or conjunctival surface 44 of the eyelid 42 when the eyelid 42 is closed. The conjunctival surface 44 slides across the entire convex surface 14 of the lens 10 as the eyelid 42 opens and closes.

The hydrophilic layer 20 of the contact lens 10 interacts with the natural tear film 16 of the eye 40 when placed on the cornea. The contact lens 10 may be located within the tear film 16 and/or reside substantially within the tear layer covering the tear film 16 of the eye 40 . In some cases, the lens 10 is immersed in the tear film 16 . The hydrophilic layer can be tailored to minimize tear film breakup caused by the contact lens.

A. Hydrophilic polymer layer

As used herein, the terms "hydrophilic layer" or "hydrogel layer" can refer to a single continuous layer or different coated portions on the lens core.

Although shown in Figure IB as a single hydrophilic layer covering both sides of the lens core, it should be understood that in some cases only a portion of the lens (eg, a single surface or a portion of a surface) may be coated with a hydrophilic polymer layer. In some cases, the hydrophilic layer may be coated on only one of the core surfaces, such as the concave surface. Furthermore, the layer does not coat the entire surface extent.

Additionally, other embodiments to be implemented may include two or more non-contiguous hydrophilic polymer layers. For example, the first hydrophilic polymer A layer may at least partially cover the concave surface, and a second hydrophilic polymer layer may at least partially cover the convex surface. Unlike the specific example shown in FIG. 1B , the first and second hydrophilic polymer layers may be in contact with each other or share a boundary.

In a specific embodiment, the arrangement between the lens core and the surrounding hydrogel or hydrophilic layer can be understood as a layered structure having a hydrophilic polymer layer attached to the outer surface of the lens core layer. The hydrophilic polymer layer can be placed on one of the concave or convex surfaces. In some variations, the hydrophilic layer may cover only a portion of the lens core layer.

In other cases, the arrangement may include a first hydrophilic polymer layer on one side of the lens core layer and a second hydrophilic polymer layer on the other side of the lens core layer. The core layer is an intermediate layer between the two hydrophilic polymer layers. The first and second layers may share a boundary (eg, a contiguous layer), or may form separate independent layers (eg, a non-adjacent layer).

The layered arrangement of the contact lenses of the present invention can be established by, for example, the fluorometric method described by Qui et al. in US Patent Applications 201200026457 and 201200026458.

In addition, the entire hydrophilic layer may have relatively uniform size, composition, and mechanical properties. Referring to FIG. 1B , the hydrophilic layer 20 has a substantially uniform thickness, water content, and chemical composition across the entire layer. In some embodiments, the hydrophilic layer has a substantially uniform composition and a substantially uniform depth and/or thickness.

It will be appreciated that uniformity is not required in all situations and may not be required. In some cases, a single layer may include different features ( including size, composition and/or mechanical properties). For example, one part of the layer can have a different thickness than other parts, which can cause the water content to vary between the two parts.

Similarly, when two or more hydrophilic layers are used, the hydrophilic polymer layers can have any common characteristics or have any different characteristics. For example, the core material can be asymmetrically layered with the hydrophilic polymer. The depth/thickness of the resulting hydrophilic polymer layer can vary between layers on the front and back of the lens substrate. This can result, for example, in different mechanical characteristics between the concave-cornea-facing side and the outward-facing convex surface of the coated contact lens.

In some variations, the average thickness of the hydrophilic polymer layer can be in the range of about 50 nm and about 500 nm. In particular embodiments, the hydrophilic layer has a thickness of about 100 nm to about 250 nm. In exemplary embodiments, the thickness of the hydrophilic layer is between about 1 micrometer and about 200 micrometers, or between about 1 micrometer and about 100 micrometers, or between about 10 micrometers and about 200 micrometers , or between about 25 microns and about 200 microns, or between about 25 microns and about 100 microns, or between about 5 microns and about 50 microns, or between about 10 microns and about 50 microns between about 10 microns and about 35 microns, or between about 10 microns and about 25 microns, or between about 1 micron and about 10 microns.

In other specific examples, the thickness of the hydrophilic layer is between about 0.01 micrometer and about 1 micrometer, or between about 0.01 micrometer and about 0.05 micrometer, or between about 0.05 micrometer and about 1 micrometer, or between about 0.01 micrometer and about 1 micrometer. between about 0.02 microns and about 0.04 microns, or between about 0.025 microns and about 0.075 microns, or between about 0.02 microns and about 0.06 microns between about 0.03 microns and about 0.06 microns. In exemplary embodiments, the average thickness of the hydrophilic layer is between about 0.01 microns and about 25 microns, or between about 0.01 microns and about 20 microns, or between about 0.01 microns and about 15 microns, or between about 0.01 microns and about 10 microns, or between about 0.01 microns and about 5 microns, or between about 0.01 microns and about 2.5 microns, or between about 0.01 microns and about 2 microns . In other variations, the average thickness of the hydrophilic layer is from about 0.1 microns to about 20 microns, or from about 0.25 microns to about 15 microns, or from about 0.5 microns to about 12.5 microns, or from about 2 microns to about 10 microns.

In other variations, the thickness or depth of the hydrogel layer can also be expressed as a multiple of the layers of the molecular monolayer. In some embodiments, the thickness of the hydrophilic layer exceeds the nominal thickness of the molecular monolayer by at least 5 times. For example, in some cases, the hydrophilic polymer layer is formed from PEG molecules having a PEG monolayer radius of about 5 nm. A PEG containing a hydrophilic polymer layer can have a thickness of about 50 nm, which forms a layer thickness or depth that is about 10 times the radius of the PEG monolayer.

Without limitation, the thickness of the anterior or posterior surfaces of the contact lenses of the present invention can be determined by AFM or fluorescence microscopic analysis of cross-sections of contact lenses in a fully hydrated state as described herein. In exemplary embodiments, the thickness of the front or back surface is at most about 30% (ie, 30% or less), or at most about 20%, of the thickness of the inner layer (eg, core) of the contact lens in a fully hydrated state % (20% or less), or up to about 10% (10% or less). In an exemplary embodiment, the thicknesses of the layers forming the front and back surfaces of the contact lenses described in this paragraph are substantially uniform. specific instance in the example In the above, the layers merge at the periphery of the contact lens to completely enclose the inner layer of the polysiloxane-containing layer.

In addition, the hydrophilic layer can be understood as having a certain volume. In some cases, the first portion of the layer has a first volume V1 and the second portion of the layer has a second volume V2. The volume can be calculated from the estimated surface area of the layer. The total volume can also be understood as the volume of a single hydrophilic layer (eg, the layer covering the entire lens) or the sum of different layers with corresponding volumes.

Volume calculations can be made based on an estimated surface area of approximately 1.25 square centimeters on each side of the lens core. In some cases, the volume of the hydrophilic polymer layer is in the range of about 15nl to about 1.5[mu]l. In other variations, a volume range of about 15n1 to about 150n1 corresponds to a thickness range of the encapsulating hydrophilic layer of about 50 nm to about 500 nm.

Additionally, in some variations, the hydrophilic layer can accommodate a tear pool comprising a portion of the tear pool volume. The total volume of the tear film is estimated to be about 4 μl to about 10 μl. For the purposes of the following calculations, an estimate of the total tear film volume was taken to be approximately 7.5 μl. Thus, in some embodiments, the hydrophilic layer can accommodate a tear pool that can comprise from about 0.2% to about 2% of the total tear pool volume.

With regard to the water content of the hydrophilic layer, in some embodiments, the water content is between about 80 wt % and about 98 wt % water. In other embodiments, the hydrophilic layer includes between about 85% and about 95% by weight water. In addition, the water content of the hydrophilic layer can be expressed as a total water content or as a weight/volume percentage. The polymer content of the hydrophilic layer can also be described in weight/volume percent.

The hydrophilic layer may also include having one or more seed populations or A hydrophilic polymer population of substances. In some cases, one or more species or subgroup systems are cross-linked to form the hydrophilic polymer layer. The hydrophilic polymer layer precursor may be provided in the form of a solution containing the crosslinkable material. Once cross-linked, the one or more species form the hydrophilic polymer coating.

In a variation, the hydrophilic layer includes a first polymer species and a second polymer species, which are at least partially cross-linked together to form the hydrophilic layer. Additionally, the polymer species or subpopulation may include linear and/or branched components. Branched species may include polymers having branch numbers ranging from 2-arm to 12-arm branches. In other specific examples, the clade species can include a star-shaped clade having about 100 or more branches.

Referring to Figure 3A, a first branched polymer species 51 and a second branched polymer species 52 are schematically shown. The first branched polymer species 51 has four branched arms with reactive functional groups A. The second branched polymer species 52 is shown to have four branching arms with reactive functional groups N. In some embodiments, the reactive moiety A of the first polymer species 51 is adapted to react with the reactive moiety B of the second polymer species 52 . The reaction between moieties A and B can form a covalent bond between the first and second polymer species. Figure 3B depicts the A-N partially crosslinked first and second species 51, 52 formed by the reaction between reactive groups A of the first polymer species and reactive groups B of the second polymer species. In some embodiments, the crosslinking between the one or more polymer and/or macromonomer species forms a hydrophilic polymer layer. For example, crosslinking one or more polymer species in a polymer solution can form a hydrogel having desirable characteristics for coating a lens core.

It will be appreciated that the crosslinking mechanism and/or reaction of the first and second polymer species may include any number of suitable methods known in the art, including photochemical or thermal crosslinking. In some cases, crosslinking can be via nucleophilic conjugation reactions, Michael-type reactions (eg, 1,4 additions) and/or clicks between individual reactive groups on more than one polymer species in the hydrophilic layer reaction occurs.

唑啉)、聚伸乙亞胺(PEI)、聚(丙烯酸)、丙烯酸聚合物，諸如聚甲基丙烯酸酯、聚電解質、玻尿酸、聚葡萄胺糖及聚葡糖所衍生之物種。 Any suitable polymer can be used as the hydrophilic polymer population in the hydrophilic layer. In some cases, the polymer population includes poly(N-isopropylacrylamide) ( PNIPAM), polypropylene amide (PAM), poly(2-

oxazoline), polyethyleneimine (PEI), poly(acrylic acid), acrylic polymers such as polymethacrylates, polyelectrolytes, hyaluronic acid, polyglucosamine and polyglucose derived species.

In addition, any suitable reactive moieties can be used as reactive functional groups (eg, reactive nucleophilic groups), including reactions to form covalent linkages between polymer species or subpopulations to form the hydrophilic polymer layer described. and electron pair acceptors) of polymer species and subpopulations.

1. Reactive functional groups

Reactive functional groups and classes of reactions that can be used for covalent bonding and cross-linking are generally known in the art. In some cases, the types of reactive functional group reactions that are useful include those performed under relatively mild conditions. These include, but are not limited to, nucleophilic substitution (eg, reaction of amines and alcohols with acyl halides and activated esters), electrophilic substitution (eg, enamine reaction), and addition to Carbon-carbon and carbon-heteroatom complex bonds (eg, Michael and Diels-Alder reactions). These and other useful reactions are discussed, for example, in: March ADVANCED ORGANIC CHEMISTRY, 3rd Edition, John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al. , MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198, American Chemical Society, Washington, D.C., 1982.

a) Amines and amine reactive groups

In a specific example, the reactive functional group is selected from an amine, such as a member of a primary or secondary amine, hydrazine, hydrazine, and sulfohydrazine. Amines can be, for example, acylated, alkylated or oxidized. Useful non-limiting examples of amine reactive groups include N-hydroxysuccinimide (NHS) esters, sulfo-NHS esters, imidoesters, isocyanates, isothiocyanates, acyl halides , aryl azides, p-nitrophenyl esters, aldehydes, sulfonic acid chlorides and carboxyl groups.

NHS esters and sulfo-NHS esters preferentially react with primary (including aromatic) amine groups of the reaction partner. It is known that the imidazolyl group of histamine competes with the primary amine used for the reaction, but the reaction product is unstable and easily hydrolyzed. The reaction involves a nucleophilic attack of the amine on the acid carboxyl of the NHS ester, releasing N-hydroxysuccinimide.

Imidoesters are the most specific acylating agents for reacting with amine groups such as proteins. At pH between 7 and 10, imidoesters Reacts only with primary amines. The primary amine nucleophilically attacks the imidate to produce intermediates that either cleave to amidines at high pH or to new imidates at low pH. The new imide esters can be reacted with other primary amines, thus crosslinking the two amine groups, which is considered as the case for a monofunctional imide ester based bifunctional reaction. The main product of the reaction with the primary amine is the amidine which is more basic than the original amine. The positive charge of the original amine group is thus retained. Therefore, the imidoester does not affect the overall charge of the conjugation.

Isocyanates (and isothiocyanates) react with a primary amine of the conjugated component to form a stable bond. Their reactions with sulfhydryl, imidazole and tyrosinyl groups yield relatively unstable products.

Acyl azide is also used as an amine group-specific reagent, where the nucleophilic amine of the reaction partner attacks the acid carboxyl group under mildly basic conditions (eg, pH 8.5).

Aryl halides such as 1,5-difluoro-2,4-dinitrobenzene react preferentially with the amine and phenolic groups of the conjugated component, but also with their mercapto and imidazole groups.

P-nitrophenyl esters of carboxylic acids are also useful amine reactive groups. Although the specificity of this reagent is not very high, the α- and ε-amine groups show the fastest response.

The aldehyde reacts with a primary amine of the conjugated component. Although unstable, a Schiff base is formed at the amine group's reactivity with an aldehyde. However, when conjugated to other double bonds, Schiff bases are stable. The resonant interaction of the two double bonds prevents the hydrolysis of the Schiff linkage. In addition, high local concentrations of amines can attack vinyl double bonds to form stable Michael addition products. Alternatively, stable bonds can be formed by reductive amination.

The aromatic sulfonyl chloride reacts with many different positions of the conjugated component, but the reaction with the amine group is the most important, forming the stable sulfonamide linkage.

The free carboxyl groups react with carbodiimides, which are soluble in both water and organic solvents, to form pseudoureas that can couple to available amines, resulting in amide linkages. For example, Yamada et al. Biochemistry 1981, 20:4836-4842 teaches how to modify proteins with carbodiimides.

b) Sulfhydryl and Sulfhydryl Reactive Groups

In other embodiments, the reactive functional group is a member selected from sulfhydryl (which can be converted to a disulfide) and a sulfhydryl reactive group. Non-limiting examples of useful sulfhydryl-reactive groups include maleimides, alkyl halides, acyl halides (including bromoacetamide or chloroacetamide), pyridyl disulfides, and sulfur Phthalimide.

Maleimide reacts preferentially with the sulfhydryl group of the conjugated component to form a stable sulfide bond. They also react with primary amine groups and imidazolyl groups in much lower yields. However, at pH 7, the maleimide can be regarded as a sulfhydryl-specific group because the reaction rate of a simple thiol at this pH is 1000 times greater than that of the corresponding amine.

Alkyl halides react with mercapto, sulfide, imidazole and amine groups. However, at neutral to weakly basic pH, alkyl halides react primarily with sulfhydryl groups to form stable thioether linkages. At higher pH, the reaction with amine groups is favored.

Pyridyl disulfides react with free sulfhydryl groups via disulfide exchange, resulting in mixed disulfides. Therefore, the pyridyl disulfide system Relatively specific thiol-reactive groups.

Sulfophthalimide reacts with free sulfhydryl groups to form disulfides.

c) Other reactive functional groups

Other example reactive functional groups include:

(a) Carboxyl and various derivatives thereof include, but are not limited to, N-hydroxybenzotriazole esters, acyl halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl groups, alkenyl groups, alkynyl groups and Aromatic esters;

(b) hydroxyl groups, which can be converted to esters, ethers, aldehydes, etc.;

(c) haloalkyl groups, wherein the halogenation can be displaced by a nucleophilic group (eg, an amine, carboxylate anion, thiol anion, carbanion, or alkoxide ion) to form a co-existence of a new group in place of the halogen atom price attached;

(d) dienophilic groups, which can participate in Diels-Alder reactions, such as, for example, maleimide groups;

(e) aldehyde or ketone groups such that subsequent derivatization is possible via the formation of carbonyl derivatives such as imines, hydrazones, hemicarbhydrazones or oximes, or via mechanisms such as Grignard addition or alkyllithium addition;

(f) alkenes, which may undergo, for example, cycloaddition, acylation, Michael addition, and the like;

(g) epoxides, which can react with, for example, amines and hydroxyl groups;

(h) phosphoramidite and other standard functional groups useful in nucleic acid synthesis; and

(i) can be used to form a structure between functionalized ligands and molecular entities or surfaces Other functional groups that form covalent bonds.

d) Reactive functional groups with non-specific reactivity

In addition to the use of position-specific reactive moieties, the present invention contemplates the use of non-specific reactive functional groups. Non-specific groups include, for example, photoactivatable groups. Photoactivatable groups are ideally inert in the dark and convert to reactive species in the presence of light. In one embodiment, the photoactivatable group may be selected from the macromonomers of nitrenes produced upon heating or photolysis of azides. Electron-deficient nitrenes are extremely reactive, and can react with a variety of different chemical bonds, including N-H, O-H, C-H, and C=C. Although three types of azides (aryl, alkyl and acyl derivatives) can be used, aryl azides are currently preferred. Aryl azides are more reactive in photolysis with N-H and O-H bonds than with C-H bonds. Electron-deficient arylazenes rapidly ring expand to form dehydroazepines, which readily react with nucleophiles rather than forming C-H insertion products. The reactivity of arylazides can be enhanced by the presence of electron-withdrawing substituents such as nitro or hydroxyl in the ring. These substituents push the arylazide absorption maxima to larger wavelengths. Unsubstituted aryl azides have absorption maxima in the range of 260-280 nm, while hydroxyl and nitro aryl azides absorb much light beyond 305 nm. Thus, hydroxy and nitroaryl azides may be preferred because they allow the use of photolysis conditions that are less harmful to the affinity component than unsubstituted aryl azides.

In an exemplary embodiment, the photoactivatable group is selected from fluorinated arylazides. The photolysis products of fluorinated arylazides are arylnitrones, which all undergo reactions characteristic of this group with high efficiency, including C-H bonds Insert (Keana et al., J. Org. Chem. 55:3640-3647, 1990).

In other embodiments, the photoactivatable groups are selected from benzophenone residues. Benzophenone reagents generally provide higher crosslinking yields than arylazide reagents.

In other embodiments, the photoactivatable groups are selected from diazo compounds, which upon photolysis form electron deficient carbenes. These carbenes undergo a wide variety of reactions, including insertion into C-H bonds, addition to double bonds (including aromatic systems), hydrogen attraction, and coordination to nucleophilic centers to provide carbon ions.

In yet other specific examples, the photoactivatable group is selected from diazopyruvate. For example, p-nitrophenyl ester of p-nitrophenyldiazopyruvate reacts with aliphatic amines to produce amide diazopyruvate which undergoes UV photolysis to form aldehydes. The photolyzed diazopyruvate modified affinity component will react like formaldehyde or glutaraldehyde.

The selection of reactive functional groups according to the reaction partner is well within the purview of those skilled in the art. As an example, activated esters such as NHS esters can be useful partners with primary amines. Thiol reactive groups such as maleimide can be useful partners with SH, thiol groups.

Additional exemplary combinations of reactive functional groups found on compounds of the invention and targeting moieties (or polymers or linkages) are set forth in Table 1.

Those skilled in the art will readily appreciate that many of these linkages can be made in a variety of ways and using a variety of conditions. Preparation of esters, see e.g. March (previous document, in 1157); preparation of thioester, see March (previous document, in 362-363, 491, 720-722, 829, 941 and 1172); preparation of carbonate, see March (previous document for details) , in 346-347); for the preparation of carbamate, see March (previous document, in 1156-57); for the preparation of amide, see March (previous document, in 1152); for the preparation of urea and thiourea , see March (previously, at 1174); for the preparation of acetals and ketals, see Greene et al. (previously, 178-210) and March (previously, at 1146); For preparation, see PRODRUGS: TOPICAL AND OCULAR DRUG DELIVERY, edited by K.B. Sloan, Marcel Dekker, Inc., New York, 1992); preparation of enol esters, see March (previously, at 1160); N-sulfonyl For the preparation of imide esters, see Bundgaard et al., J. Med. Chem., 31: 2066 (1988)); 91 and 1154); for the preparation of N-acylamide, see March (in 379 above); for the preparation of N-Mannich bases, see in March (in 800-02 and 828); For the preparation of methyl ketoesters, see Petracek et al., Annals NY Acad. Sci., 507:353-54 (1987)); for the preparation of disulfides, see March (previously, at 1160); and phosphonic acids Esters/esters and phosphonamidates.

Reactive functional groups can be selected such that they do not participate in or interfere with the reactions necessary to assemble the reactive ligand analog. Alternatively, reactive functional groups can be protected from participation in the reaction by the presence of protecting groups. Those skilled in the art will understand how to protect specific functional groups from interfering with selected group of reaction conditions. Examples of useful protecting groups are detailed in Greene et al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley & Sons, New York, 1991.

In general, at least one of these chemical functional groups can be activated prior to the formation of linkages between the compounds of the invention and the calibration (or other) reagents and optional linking groups. Those skilled in the art will understand that various chemical functional groups, including hydroxyl, amine, and carboxyl groups, can be activated using a variety of standard methods and conditions. For example, the hydroxyl group of the ligand (or calibrator) can be activated by treatment with phosgene to form the corresponding chloroformate, or by treatment with p-nitrophenyl p-chloroformate to form the corresponding carbonate.

In an exemplary embodiment, the present invention utilizes a calibrator that includes carboxyl functional groups. Carboxyl groups can be activated, for example, by conversion to the corresponding acyl halide or active ester. This reaction can be carried out under various conditions as described in March, supra pp. 388-89. In an exemplary embodiment, the acyl halide is prepared via the reaction of a carboxyl-containing group with oxalyl chloride. The activator is combined with a ligand or ligand-linker arm combination to form the conjugate of the present invention. Those skilled in the art will appreciate that the use of carboxyl-containing calibration agents is for illustration only, and that agents with many other functional groups can be conjugated to the ligands of the present invention.

Referring to Figure 4A, in some embodiments, reactive functional groups include thiol and sulfonyl moieties. The reactive nucleophilic group may be a thiol group suitable for reaction to a sulfonyl group as an electron pair accepting moiety. When the first polymer species contains thiol groups and the second polymer species contains reactive sulfonyl groups, the covalent linkage between the first and second species can be via a thioether moiety formed (Fig. 4B).

In other variations, one or more polymer species in the hydrophilic layer are covalently linked via sulfonyl moieties such as, but not limited to, alkylene sulfonyl moieties, dimeryl moieties, An alkylsulfonyl moiety, an ethylenylsulfonyl moiety, or a dipethenylsulfonyl moiety. In other variations, one or more polymer species in the hydrophilic layer is via a sulfonyl moiety and a thioether moiety, or via an alkylenesulfonyl moiety and a thioether moiety, or via a dialkenylsulfonyl moiety The base moiety and the thioether moiety are covalently linked, either via an ethylenylsulfonyl moiety and a thioether moiety, or via a dipethenylsulfonyl moiety and a thioether moiety.

In other variations, one or more polymer species in the hydrophilic layer is via an ester moiety, or via an alkane diester moiety, or via a ethylene diester moiety, or via a thioether moiety, or via an ester moiety and a thioether moiety , or covalently linked via an alkane diester moiety and a thioether moiety, or via a glycol diester moiety and a thioether moiety.

In some embodiments, the ratio of reactive subpopulations in the hydrophilic polymer population is about 1 to 1. In other specific examples, the concentration of one of the subpopulations or species exceeds that of the other species by about 10% to about 30%. For example, the concentration of polymer species with electron pair accepting moieties can exceed other polymer species with reactive nucleophilic groups.

Additionally, when the concentrations of the first and second polymer species are about 1 to 1, the relative amounts of reactive moieties for each species can be about the same or different. For example, polymer species may have a greater number of reactive sites with electron docking than other polymer species bearing nucleophilic groups Subject to the location of the part. This can be achieved, for example, by having a first branched polymer species with more arms with reactive electron pair accepting sites than a second polymer species with a nucleophilic moiety.

2. PEG-containing hydrophilic layer

In some embodiments, the polymer in the hydrophilic layer comprises polyethylene glycol (PEG). The PEG can include species with molecular weights between about 1 kDa and about 40 kDa. In particular embodiments, the molecular weight of the PEG species is between about 5 kDa and about 30 kDa. In some embodiments, the hydrophilic polymer population consists of a species of polyethylene glycol (PEG). In other variations, the weight average molecular weight MW of the PEG polymer having at least one amine or carboxyl or thiol group or vinyl group or acrylate moiety (as a hydrophilicity _enhancer ) may be from about 500 to about 1,000,000, or From about 1,000 to about 500,000. In other specific examples, the population of hydrophilic polymers comprises different PEG species.

In some cases, the polymer includes subunits of PEG. In some variations, the subunits of the polymer of the PEG-containing layer of the contact lens are at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or at least about 99.5% % polyethylene glycol.

In some cases, the water content of the PEG-containing hydrophilic layer is between about 80 wt% and about 98 wt% water. In other embodiments, the hydrophilic layer includes between about 85% and about 95% by weight water.

The PEG-containing hydrophilic layer may comprise a PEG hydrogel having a swelling ratio. To determine the swelling ratio, the PEG hydrogel can be weighed immediately after polymerization , and then immerse it in distilled water for a period of time. The swollen PEG hydrogel was weighed again to determine the amount of water absorbed into the polymer network to determine the swelling ratio. Mass fold increase can also be determined from the comparison before and after the water swelling. In some embodiments, the combined mass increase of the PEG-containing layer is less than about 10%, or less than about 8%, or less than about 6%, or less than about 5%, or less than about 4%, or less than About 3%, or less than about 2%, or less than about 1%. In some cases, the combined increase in mass is measured by weighing the wetted hydrogel and then drying and weighing it again. The mass is then combined and added to the swollen weight minus the dry weight divided by the swollen weight. As a hydrophilic layer rather than a monolithic hydrogel, this can be achieved by coating a non-hydrated substrate followed by mass change calculations.

In other aspects, the present invention provides a hydrophilic layer having two cross-linkable PEG species. The first PEG species may include reactive functional groups suitable for reaction to other reactive functionalities on the second PEG species. Any of the functional groups described (eg, previous moiety (A)(1)) may be suitable for forming crosslinks between the first and second PEG species.

In some cases, the first PEG species includes an electron pair accepting moiety, and the second PEG species can include a reactive nucleophilic moiety. Once cross-linked via the reaction between the electron pair accepting moiety and the nucleophilic moiety, the PEG polymer network forms a hydrogel with a certain water content or concentration. PEG hydrogels can be used as hydrophilic layers to coat contact lenses to provide improved wettability, wearability, and/or reduced tear film rupture.

3. Active agent

The hydrophilic polymer layer may include active agents such as any or more of pharmaceutical agents, UV absorbers, visibility colorants, antimicrobial agents, bioactive agents, leachable lubricants, leachable tear stabilizers, or mixtures thereof . These substances and materials can be deposited on the contact lens to enhance the interaction of the contact lens with the eye area. Such substances may consist of polymers, pharmaceutical agents or any other suitable substances and may be used to treat various ocular pathologies including, but not limited to, dry eye, glaucoma, corneal ulcers, scleritis, keratitis, iritis and corneal vasculitis hyperplasia.

4. Interpenetrating polymer network structure

The outer hydrogel network is also composed of interpenetrating polymer networks (or semi-interpenetrating polymer networks) formed in simultaneous or sequential polymerizing steps. For example, when forming the initial outer hydrogel layer, the layer can be swelled in a monomer solution, such as acrylic acid, along with the crosslinker and initiator. When exposed to UV light, a second interpenetrating network will form. The dual mesh structure imparts additional mechanical strength and durability while maintaining high water content and high wettability.

B. Lens core

Any suitable contact lens can be used as the lens core for coating with the hydrophilic polymer layer. For example, the lens core can be hydrophobic or hydrophilic. The hydrophilic core may have a suitable water content but lack the protein binding resistance imparted by the hydrophilic layer to be implemented. The hydrophilic core can include a hydrogel-containing core, such as a pure hydrogel lens. For example, the core can contain There are polyhexyl ethyl methacrylate lenses (pHEMA).

Suitable hydrophobic cores include lenses with high polysiloxane content. The lens core may be composed of substantially entirely pure polysiloxane, ie, the core contains about 100 wt% polysiloxane. In other instances, the lens core, matrix or substrate comprises from about 10 to about 50 weight polysiloxane. In some cases, the substrate or core includes about 25 wt% polysiloxane.

In other embodiments, the lens core may contain a polysiloxane hydrogel (SiHy), wherein the core is more hydrophilic than a pure polysiloxane core, but less than a pure hydrogel. In these cases, the SiHy lens core can be coated with the hydrophilic polymer layer to improve the wettability and wearability of the core. In other variations, the core comprises from about 10% to about 20% by weight polysiloxane.

In an exemplary embodiment, the polysiloxane-containing layer or core of the coated contact lens is Latrofilcon, balafilcon, galyfilcon, senofilcon, narafilcon, omafilcon, comfilcon, enfilcon or asmofilcon. In some cases, the polysiloxane-containing core is NuSil Med 6755.

Alternatively, a non-silicone-based core can be used as the substrate for coating. For example, oxygen permeable lenses made from non-silicone materials can also be coated with the hydrophilic layer.

In an exemplary embodiment, the core or core layer has a thickness of about 0.1 microns to about 200 microns, or about 1 micron to about 150 microns, or about 10 microns to about 100 microns, or about 20 microns to about 80 microns. microns, or from about 25 microns to about 75 microns, or from about 40 microns to about 60 microns.

C. Attachment of the hydrophilic layer to the core

Another aspect of the present invention provides coated contact lenses having a hydrophilic polymer layer covalently linked and attached to the core. The covalent bonding between the hydrophilic layer and the core can be understood as a bonding moiety covalently arranged between the lens core and the hydrophilic layer. In some cases, the linking moiety covalently attaches the hydrophilic layer to the outer surface of the lens core.

In some embodiments, the linking moiety can include at least any of the reactive functional groups described in section (A)(1). In other variations, the linking moiety may be the resulting moiety formed by the reaction between at least one or more of the reactive functional groups described in section (A)(1). For example, the linking moiety can include an electron pair accepting group, such as a Michael-type Michael-type electron pair acceptor (eg, a sulfonyl group) on the polymer species in the hydrophilic layer, which reacts to covalently bind the hydrophilic polymer layer Attached to the core.

Advantageously, the hydrophilic polymer layer can be attached to the core via a similar reaction used to crosslink the hydrophilic polymer layer. 5A-5C, the hydrophilic polymer layer includes a first polymer species P1 having reactive groups A and a second polymer species P2 having reactive groups N1. As previously described, the hydrophilic polymer layer can be formed by crosslinking the first polymer species and the second polymer species through the reaction between reactive groups A and N1. As shown in FIG. 5A , the covalent linkage 63 covalently bonds the first and second species to form a first hydrophilic polymer layer 70A on the convex surface 64 and A second hydrophilic polymer layer 70B is formed on the concave surface 62 of the lens core 60 .

With continued reference to Figure 5A, the first polymer species also forms covalent bonds 61 with the outer surface of the core. As shown, a covalent bond is formed via the first polymer species P1 and reactive groups A on the surface of the core. In some embodiments, the reactive group A on the first polymer species P1 reacts to (1) crosslink the polymer species in the hydrophilic polymer layer and (2) the hydrophilic polymer layer to be formed attached to the core. In these cases, this causes the A part of the first part to react with the N1 part and the A part of the second part to react with the core surface. In some cases, the concentration of the first polymer species P1 and/or the amount of available reactive A moieties for the first polymer species exceeds the corresponding concentration and/or available reactive N1 moieties of the second polymer species.

Referring to Figure 5B, the lens core may include reactive moieties N2. The reactive moiety N2 may be adapted to react with the reactive groups of the polymer species in the hydrophilic polymer layer. In some cases, the reactive moiety N2 reacts to only one of the polymer species. Referring to Figure 5C, the reactive moiety N2 reacts with the reactive group A on the first species P1 to form a covalent attachment between the hydrophilic polymer layer and the core.

It will be appreciated that the reaction for attaching the hydrophilic polymer layer to the core may include any number of methods known in the art, including at least those described in section (A)(1). In some cases, the covalent linkage is via nucleophilic conjugation reactions, Michael-type reactions (eg, 1,4 additions) and/or between individual reactive groups on more than one polymer species in the hydrophilic layer Occurs in response to a click.

In some cases, the reactive A group is an electron pair acceptor, and the reactive groups N1 and N2 are reactive nucleophilic groups. N1 and N2 can be the same or different reactive groups. Continuing to refer to the example shown in Figures 5A-5C, the hydrophilic polymer layer is formed by the first reaction between the reactive A group and the reactive nucleophile N1. Furthermore, the hydrophilic polymer layer is covalently attached to the core via a second reaction between the reactive A groups and the nucleophile N2. The two reactions can take place simultaneously or nearly simultaneously in the same reaction vessel.

When the reactive functional group includes thiol and sulfonyl moieties, the reactive A group can be a sulfonyl group on the first PEG macromonomer. The moiety acts as an electron pair accepting moiety on the first PEG macromonomer. The reactive nucleophiles N1 and/or N2 may be thiol groups (see Figure 4A). For the first reaction, the first and second PEG macromonomers form crosslinks via reactive thiol and sulfonyl groups that can form thioether moieties (see Figure 4B). When the N2 nucleophile on the core is also a thiol group, a thioether can also be formed by the reaction between the sulfonyl moiety on the first PEG macromonomer and N2 on the surface of the lens core.

It will be appreciated that the nucleophilic groups (or other types of reactive groups) on the core need not be the same as the reactive groups in the hydrophilic polymer layer. However, the use of the same reactive groups can provide many advantages, such as controllability or predictability of individual reactions.

In other variations, the hydrophilic polymer layer is covalently bonded to the lens core via a sulfonyl moiety such as, but not limited to, an alkylenesulfonyl moiety, a dialkylenesulfonyl moiety Partially, Ethylene Sulfonate The acyl moiety or the dipethenyl sulfonyl moiety. In other variations, the hydrophilic polymer layer is via a sulfonyl moiety and a thioether moiety, or via an alkylenesulfonyl moiety and a thioether moiety, or via a dialkylenesulfonyl moiety and a thioether moiety, or Covalent attachment to the core is via an ethylsulfonyl moiety and a thioether moiety, or via a dipethenesulfonyl moiety and a thioether moiety.

In other variations, the hydrophilic polymer layer is via an ester moiety, or via an alkane diester moiety, or via an ethylene diester moiety, or via a thioether moiety, or via an ester moiety and a thioether moiety, or via an alkane diester moiety and A thioether moiety, or covalently attached to the core via a glycolate moiety and a thioether moiety.

In other embodiments, the bond between the core lens and the hydrophilic layer is covalently bonded, specifically excluding any other form of chemical bond or association. For example, the hydrogel layer as described above can be bound to the surface of the hydrophobic lens by chemical bonds consisting of covalent bonds.

D. Multilayer Contact Lenses

In some embodiments, the coated contact lenses contemplated herein are layered lenses having a hydrophilic polymer layer on a polysiloxane-containing layer. Some variations provide a polysiloxane-containing layer and a first polyethylene glycol-containing layer, wherein the first polyethylene glycol-containing layer and the polysiloxane-containing layer are covalently attached to each other, and the contact lens has a layered structure structure. In an exemplary embodiment, the contact lens does not include a second polysiloxane-containing layer. In other specific examples, the contact lens does not include a second polyethylene glycol-containing layer. In other embodiments, the contact lens does not include a second polysiloxane-containing layer or a second polyethylene glycol-containing layer. In an exemplary embodiment, a contact lens includes an anterior surface and a posterior surface, wherein the anterior surface is The first polyethylene glycol-containing layer, and the rear surface is a polysiloxane-containing layer. In an exemplary embodiment, the contact lens includes a front surface and a back surface, wherein the front surface is a polysiloxane-containing layer, and the back surface is a first polyethylene glycol-containing layer.

In an exemplary embodiment, the layer forming the front surface of the contact lens and the layer forming the back surface are substantially the same thickness. In other cases, the layers may independently have any suitable thickness, including those described above for the hydrogel layer or core.

In other aspects, the present invention provides contact lenses comprising a polysiloxane-containing layer, a first polyethylene glycol-containing layer, and a second polyethylene glycol-containing layer, wherein the first polyethylene glycol-containing layer and the polysilicon-containing layer The oxygen layers are covalently attached to each other, the second polyethylene glycol-containing layer and the polysiloxane-containing layer are covalently attached to each other, and the contact lens has a layered structure. In an exemplary embodiment, the contact lens does not include a second polysiloxane-containing layer. In an exemplary embodiment, the contact lens does not include a third polyethylene glycol-containing layer. In exemplary embodiments, the contact lens does not include a second polysiloxane-containing layer or a third polyethylene glycol-containing layer. In an exemplary embodiment, a contact lens includes an anterior surface and a posterior surface, wherein the anterior surface is a first polyethylene glycol-containing layer and the posterior surface is a second polyethylene glycol-containing layer. In an exemplary embodiment, the contact lens described in this paragraph includes an anterior surface and a posterior surface, wherein the anterior surface is a first polyethylene glycol-containing layer, the posterior surface is a second polyethylene glycol-containing layer, and the The first and second polyethylene glycol-containing layers are substantially identical to each other. In other instances, the first polyethylene glycol-containing layer has compositions, dimensions, or other characteristics independent of the second polyethylene glycol-containing layer.

In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are via a sulfonic acid base Part Covalently Attached. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an alkylene sulfonyl moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a dialkenylsulfonyl moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an ethylsulfonyl moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a dipethenesulfonyl moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a thioether moiety.

In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a sulfonyl moiety and a thioether moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an alkylene sulfonyl moiety and a thioether moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a dialkenylsulfonyl moiety and a thioether moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an ethylsulfonyl moiety and a thioether moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a dipethenylsulfonyl moiety and a thioether moiety.

In an exemplary embodiment, with respect to any contact lens of the present invention In one aspect, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a sulfonyl moiety. In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an alkylene sulfonyl moiety. In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a dialkenylsulfonyl moiety. In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an ethylsulfonyl moiety. In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a dipethenesulfonyl moiety. In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a thioether moiety.

In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a sulfonyl moiety and a thioether moiety. In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an alkylene sulfonyl moiety and a thioether moiety. In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a dialkenylsulfonyl moiety and a thioether moiety. In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an ethylsulfonyl moiety and a thioether moiety. In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a dipethenyl sulfonyl moiety and a thioether moiety.

In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an ester moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an alkylene ester moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an ethylidene ester moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via a thioether moiety.

In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an ester moiety and a thioether moiety. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via alkylene ester moieties and thioether moieties. In an exemplary embodiment, for any of the present contact lenses, the first polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an ethylidene ester moiety and a thioether moiety.

In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an ester moiety and a thioether moiety. In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via alkylene ester moieties and thioether moieties. In an exemplary embodiment, for any of the present contact lenses, the second polyethylene glycol layer and the polysiloxane-containing layer are covalently attached via an ethylidene ester moiety and a thioether moiety.

E. Contact angle

Advantageously, some coated contact lenses to be practiced provide hydrophilic polymer layers having a population of hydrophilic polymers that are cross-linked to each other and in addition covalently attached as a whole to the lens core or layer. As such, the hydrophilic polymer layer can improve the wettability of the core contact lens.

As described in more detail below, the hydrophilicity or wettability of the hydrogel layer can be measured by a contact angle goniometer implementing a method known as the trapped bubble contact angle test. Relatively high hydrophilicity systems are associated with relatively low advancing contact angles.

In a typical embodiment of a contact lens according to the disclosed technology, when the lens is subjected to a bubble contact angle test, the lens exhibits advance contact in the range of about 20° to about 50°. In a more specific embodiment, the lens exhibits advancing contact within the range of about 25° to about 35°.

Figures 6A-6C show aspects of the trapped air bubble test commonly used in the contact lens industry as a proxy measure for wettability or hydrophilicity of contact lenses, as provided by specific examples of this technique. Figure 6A shows the setup 100 for the trapped bubble test. Setup 100 includes lens holding fixture 102 in communication with test lens 104 . Air bubbles 106 originate from syringe pump 108 on the surface of the test lens.

Figure 6B shows a schematic diagram of the contact angle in an aqueous solution between a contact lens surface and a bubble as the bubble expands against the contact lens or is pulled away from the contact lens.

Figure 6C provides a series of schematic diagrams that are produced when a bubble expands against the surface of a contact lens and is then pulled away. The test is depicted on the left side of the figure the "backward phase" of the test; the right side of the figure depicts the "forward phase" of the test. On the left, the bubbles first come into contact with what would be the central point of contact between the bubble and the contact lens, the mutual contact area expands, and the surrounding water space recedes from this central point of contact. Therefore, it is called the "backward phase". On the right, as the bubble is pulled away, the aqueous solution advances towards the central point of contact between the bubble and the contact lens. Therefore, it is called the "advance phase" of the test. These shapes can be videotaped during testing to capture this dynamic. In the recorded video, software-based edge detection and angle separation techniques can be used to measure the receding and advancing angles at the interface between the bubble and the lens.

The small angle reflects the relatively high affinity of the contact lens surface for water rather than air, both in advance and retreat in this test. Thus, there is a correlation between a small contact angle and the hydrophilicity or wettability of the contact lens surface. Conversely, the large contact angle reflects the relative lack of affinity of the contact lens surface for water. With this test, the hydrophilicity of specific examples of contact lenses of this technology can be quantified.

In exemplary embodiments, the contact lens having the hydrophilic polymer layer as described has an advancing contact angle of at least 20 degrees, or at least 25 degrees, or at least 30 degrees, or at least 35 degrees, or at least 40 degrees. In other specific examples, the advancing contact angle is between about 20 degrees and about 40 degrees, or between about 20 degrees and about 35 degrees, or between about 20 degrees and about 30 degrees, or in between between about 20 degrees and about 25 degrees, or between about 25 degrees and about 40 degrees, or between about 25 degrees and about 35 degrees, or between about 25 degrees and about 30 degrees, Either between about 30 degrees and about 40 degrees, or between about 35 and about 40 degrees. In other variations, the advancing contact angle is to About 8 degrees less, or at least about 9 degrees, or at least about 10 degrees, or at least about 11 degrees, or at least about 12 degrees, or at least about 13 degrees. In exemplary embodiments, the advancing contact angle is between about 8 degrees and about 20 degrees, or between about 8 degrees and about 17 degrees, or between about 8 degrees and about 14 degrees, between between about 8 degrees and about 12 degrees, or between about 9 degrees and about 20 degrees, or between about 9 degrees and about 17 degrees, or between about 9 degrees and about 14 degrees, between between about 9 degrees and about 12 degrees, or between about 10 degrees and about 20 degrees, or between about 10 degrees and about 17 degrees, or between about 10 degrees and about 14 degrees, between about 10 degrees and about 12 degrees, or between about 11 degrees and about 20 degrees, or between about 11 degrees and about 17 degrees, or between about 11 degrees and about 14 degrees .

F. METHODS OF MAKING COATED CONTACT LENSES OR MULTI-LAYER CONTACT LENSES

Other aspects of the present invention provide methods of making such coated and/or layered contact lenses.

In some embodiments, the method includes the step of reacting the contact lens surface with the hydrophilic polymer solution. The hydrophilic polymer solution may contain one or more subpopulations or species suitable for reaction to form a coating on at least a portion of the contact lens. In some cases, the hydrophilic polymer solution reacts to form a crosslinked coating on the contact lens. The coating may be partially or substantially fully cross-linked.

As shown in FIG. 3A, the hydrophilic polymer solution may include a first polymer species having reactive groups A and a second polymer species having reactive groups N. The hydrophilic polymer layer can react on the first and second The reactive groups on the dipolymer species are formed to form a crosslinked hydrophilic polymer layer. As shown in Figure 3B, the reactive groups A and N can form a covalent bond 54 between the first and second polymer species, thereby crosslinking the two species and forming a hydrophilic polymer layer. In some cases, the reaction between the first and second reactive groups on the individual polymer species forms a hydrogel.

As described, any suitable reaction is used to form the hydrophilic polymer layer. Such reactions include, but are not limited to, nucleophilic conjugation reactions, Michael-type reactions (eg, 1,4 nucleophilic addition reactions), and/or click reactions. In some cases, the reactive groups A and N are an electron pair accepting moiety and a nucleophilic moiety, respectively.

Additionally, in some variations, the polymer species or subpopulation in the hydrophilic polymer layer can include PEG species. In some cases, the first PEG species reacts with the second PEG species to form a hydrophilic polymer layer. For example, the first PEG species may include a nucleophilic reactive moiety electron pair acceptor suitable for reaction to the second PEG species to covalently bond the PEG species.

Some specific examples provide covalent attachment between the hydrophilic polymer layer and the lens core or layer. For example, one or more polymer subpopulations or species in a hydrophilic polymer layer or solution can be adapted to react to the lens core to form a covalent attachment between the hydrophilic layer and the lens core. In some cases, the method of hydrophilic polymer layer attachment includes the step of reacting at least one of the polymer species with reactive sites on the core surface to form a space between the polymer species and the core surface the covalent bond.

Referring again to FIGS. 5A-5C , the first polymer species P1 may include reactive groups suitable for reaction to reactive groups N2 on the surface of the core 60 A. The reaction between the A and N2 groups forms a covalent bond 61 between the first polymer species P1 and the core 60 . As shown, the reactive group A may also be suitable to react with other reactive moieties N1 of the second polymer species P2 to form a hydrophilic polymer layer. As such, the first reaction between P1 and P2 forms a hydrophilic polymer layer, and the second reaction couples the hydrophilic polymer layer to the core.

In some cases, the same reactive group A on the first polymer species P1 can react to the reactive moiety N1 or N2. In a variation, the first portion of reactive A groups react to the N1 moiety, and the second portion of the reactive groups react to the N2 moiety. In some embodiments, the first and second moieties of reactive A groups are on the same molecule of the polymer species. In other variations, the first and second moieties of the reactive A groups are on different branching arms of the same polymer species. The dual reactions between P1 and P2 and between P1 and the core can occur in the same reaction vessel and during the same reaction time (or a partial overlap of the reaction time).

As noted, any suitable reaction can be used to form and attach the hydrophilic polymer layer to the lens core. Such reactions include, but are not limited to, nucleophilic conjugation reactions, Michael-type reactions (eg, 1,4 nucleophilic addition reactions), and/or click reactions. For example, the plurality of reactions can all be nucleophilic conjugation reactions. Alternatively, the plurality of reactions may be different reactions.

In some embodiments, the first and second reactions may be nucleophilic conjugation reactions, and more particularly, both are 1,4-nucleophilic addition Michael-type reactions. For example, in some embodiments, the nucleophilic reactive moieties of the first population of macromonomers comprise thiol groups, while the The electron pair accepting moiety contains a base.

In other embodiments of this method, the first and second nucleophilic conjugation reactions can be more broadly described as "click" type reactions. As originally described by Karl Sharpless et al., a click reaction is one that typically occurs in an aqueous environment, is accomplished in high yields driven by large thermodynamic forces, and produces substantially no by-products or by-products that are nontoxic to biological systems. Modular composition of molecules. Click reactions are advantageous for applications in the manufacture of contact lenses because these lenses can be reacted in rapid aqueous solutions without toxic by-products and in high yields.

之間的[4+1]環加成，(e)特別針對小應變環(如環氧化合物及氮

化合物)之親核取代，(f)脲之似羰基化學性質形成，及(g)至碳-碳雙鍵之加成反應，諸如涉及雙羥化或硫醇炔(thiolyne)反應中之炔。 Other examples of click-type reactions that can be used in the immersion dip coating method of the present invention to attach branched polymers include (a) generally general thiol-ene click reactions, (b) [3+2] cycloadditions, Including Huisgen 1,2-dipolar cycloaddition, (c) Diels-Alder reaction, (d) between isonitrile (H) and tetra

[4+1] cycloaddition between, (e) especially for small strained rings such as epoxides and nitrogen

Compounds) nucleophilic substitution, (f) carbonyl-like chemical formation of urea, and (g) addition reactions to carbon-carbon double bonds, such as alkynes involving bishydroxylation or thiolyne reactions.

In a particular embodiment, the method of making a coated lens comprises the steps of: reacting the outer surface of the contact lens with a first PEG species of a hydrophilic polymer solution, wherein the first PEG species comprises an electron pair accepting moiety , and the first portion of the electron pair-accepting moiety forms a covalent attachment to the outer surface of the contact lens via a first nucleophilic conjugation reaction; and the first PEG species of the hydrophilic polymer solution and the hydrophilic reaction of a second PEG species of the polymer solution, the second PEG species comprising is adapted to covalently bond to a second moiety of the electron pair accepting moiety of the first PEG species in a second nucleophilic conjugation reaction to at least partially crosslink the nucleophilic reactive moieties of the first and second PEG species, wherein The PEG hydrogel coating is formed and attached to the outer surface of the contact lens by the first and second nucleophilic covalent reactions.

In other specific examples, the method includes activating the lens core surface. The activated surface can form a plurality of chemically reactive sites on the surface. The reactive site can be, for example, a nucleophilic site that reacts with a hydrophilic polymer.

Referring to Figure 7, a lens 160 with no reactive sites is shown to have a plurality of reactive sites 162 after an activation or modification procedure. In some cases, a plasma process is used to activate the surface of the core lens. The activation procedure may include the step of exposing the outer surface of the lens core to a gas plasma. In some embodiments, the lens is transferred to a fixture (usually metal) and placed in a vacuum plasma chamber. The lens is plasma treated in an atmospheric plasma to form reactive sites on the surface. In some cases, ambient plasma was applied at 200 mTorr for about 3 minutes to form nucleophilic functional sites on the lens. In some embodiments, the lenses are dehydrated prior to plasma treatment.

In other variations, the contact lens surface can be activated by plasma treatment, preferably in oxygen or nitrogen. For example, the procedure to be performed may include activating the core material in a nitrogen plasma.

In other embodiments, activation of the contact lens surface can also occur via exposure to elevated pH (eg, solution pH above 11).

In other embodiments, activation also occurs by modifying the monomer mixture to include groups reactive with the branched hydrophilic coating polymer. Activation of the monomer mixture can be direct activation, or activation using protecting groups that are cleaved by light or pH change. In other cases, plasma polymerization of functional silanes including mercapto and amino silanes can be used for activation. In addition, plasma polymerization of allyl alcohol and allylamine can also be used for activation.

In some embodiments, the core activation or modification step forms reactive groups N2 (shown in Figure 5B) that can react with at least one of the polymer species of the hydrophilic polymer layer. In some cases, at least one of the polymer species in the hydrophilic polymer layer reacts with a portion of the plurality of reactive sites on the outer surface of the core to form a co-polymer between the hydrophilic polymer layer and the core surface Price attached. In some cases, the lens core is activated prior to forming a hydrophilic polymer layer on the surface of the core.

In some embodiments, the method of making a coated lens includes the step of reacting an activated core surface with a population of functionalized hydrophilic polymers. For example, a hydrophilic polymer can include a population of functionalized branched hydrophilic macromonomers having a first subpopulation functionalized with a nucleophilic reactive moiety and a second subpopulation functionalized with an electron pair accepting moiety. In other embodiments, the method can include reacting functional moieties of two subpopulations of macromonomers with each other in a first nucleophilic conjugation reaction to form a covalent linkage between the two subpopulations of macromonomers, Thereby, a crosslinked polymer network is formed.

The method may also include reacting the electron pair accepting moiety and the activated lens core surface of the second macromonomer subpopulation in a second nucleophilic conjugation reaction The nucleophilic moiety of the face to covalently attach the electron pair accepting moiety to the lens core surface. When the first and second nucleophilic conjugation reactions are complete, a contact lens with a lens core to which a crosslinked hydrophilic hydrogel layer is covalently attached is produced.

As noted, the first and second nucleophilic conjugation reactions may be of the same type, the reactions differing by having different reactants. Both reactions can include the same electron pair acceptor, such as a hydrophilic polymer species comprising electron pair acceptors that can participate in multiple reactions. The plurality of reactions may differ by having distinctly different nucleophilic reactive parent molecules, in one instance a hydrophilic polymer species having a nucleophilic moiety, and in a second instance a lens core having a nucleophilic moiety Polysiloxane is the polymer of the substrate.

Referring to Figure 8, a schematic 200 of two example conjugation reactions 214, 216 and main reactants is shown. The main reactants can be understood as the nucleophilic moiety 202 and the electron pair accepting moiety 204 . In the first reaction, a reactant with a nucleophilic functional moiety (such as PEG-thiol 206) is reacted with a reactant with an electron pair accepting functional moiety 204 (PEG-Two 204); the product of reaction 214 is a bond of PEG molecules pair, which are linked via a central thioether bond. Since the reaction takes place in functionalized PEG molecules, the PEG is in the form of a bonded network, and because the PEG network is hydrophilic, the network is in the form of an integrated hydrogel in an aqueous environment.

In a second reaction 216, a reactant 204 having an electron-pair accepting functional moiety, such as PEG-Two 204, reacts with nucleophilic sites on the surface of the raw-substrate lens core 210; the product of this second reaction 216 is in A covalent bond between the PEG-D and the lens core. As mentioned above, since Also included are individual molecules covalently bonded to the core of the activated polysiloxane as a component of the hydrogel structure, which as a whole becomes a covalently bonded lens core.

9A-9D show more detailed and specific aspects of the reactants and reactions, as depicted schematically in FIG. 8 . Figure 9A shows that a polysiloxane-based lens core is activated by plasma treatment to produce a lens surface covered with a bed of activated nucleophilic sites. Figure 9B shows the structure of an example of a reactant including a PEG molecule, a Michael-type electron acceptor (such as a vinyl susceptor moiety), a nucleophile functional group (such as a thiol group), and details of the Michael-type reaction itself.

Figures 9C-9D show where two branched hydrophilic polymer species--a first subpopulation with nucleophilic functional groups (N) and a second subpopulated with electron pair accepting functional groups (A)--were treated during immersion Reaction procedure in reaction solution for nucleophilic activation (N) of the lens core. In the lower part of Figure 9D, according to the first reaction depicted in Figure 8, the reactive individual members of the two subpopulations start to bond together via their functional groups to form a hydrogel network. And, according to the second reaction depicted in Figure 8, the electron pair accepting moiety (A) of the hydrophilic polymer participates in covalent bonding with nucleophilic sites on the lens surface, thereby covalently covalently bonding the hydrogel network Bonded to the lens surface.

10A-10B provide flow diagrams of two procedural variations for making contact lenses with covalently attached hydrogel films. Figure 10A shows a procedure including a plasma activation method. Such plasma treatment may include exposure to either an oxygen plasma or a nitrogen plasma. Figure 10B shows a procedure including chemical or "wet" activation methods.

Contact lens 320 is plasma treated as shown in FIG. 10A 324 to form a plurality of reaction sites on the contact lens. This can be done by placing the lens in a vacuum plasma chamber. In some embodiments, the lens is transferred to a fixture (usually metal) and placed in a vacuum plasma chamber. The lenses were plasma treated in an ambient plasma at 200 mTorr for about 3 minutes to create nucleophilic functional sites on the lenses. As mentioned, the lenses can be in a dehydrated state prior to plasma treatment.

With continued reference to FIG. 10A, after the lens core is activated, the activated lens core is placed into a solution 324 that includes a coating polymer and/or coating a polymer species or precursor. The coating polymer can be any of the hydrophilic polymers described including a population of hydrophilic polymers comprising a sub-population of functionalized branched PEG species. In some cases, the solution also includes isopropanol and water. The solution may have a pH>7. The solution can be agitated to produce a well-stirred bath, and the lenses are incubated in the solution for a period of time. In some cases, the incubation time is about 50 minutes.

Optionally, the coating procedure may include an extraction step to remove unwanted components from the coated lens. For example, when a polysiloxane-based lens core is used as a matrix or substrate, unreacted polysiloxane molecules in the lens core are extracted or diffused out of the lens. Advantageously, the extraction process removes virgin lens core material (eg, virgin polysiloxane for a polysiloxane-containing core) that can leach from the lens to the eye area. As such, other steps of the procedure may include transferring the lens to a solution of isopropanol and water for a period of time (such as about 50 minutes) 326 to continue to extract unreacted polysiloxane molecules from the lens core. Additionally, as a second wash 328, the lens can be transferred to a fresh solution of isopropyl alcohol and water for a period of time (such as about 50 minutes) to further remove the lens core step to extract unreacted polysiloxane molecules. In some variations, the lens may also be transferred to a water bath 330 to equilibrate in water for a period of time (eg, about 50 minutes).

Alternatively, as shown in Figure 10A, the lens can be transferred to a packaging container 332 with a packaging solution. Lenses can also be autoclaved 334. In some cases, the lenses are autoclaved at about 250°F for about 30 minutes.

Figure 10B depicts a wet activation procedure for activating the lens core and coating the activated core. The procedure may begin 370 with the lens in a hydrated state. The next step may include activating the hydrated surface lens core 372. This can be done by plasma or chemical treatment. For example, ozone can be used to activate the core surface. Once activated, the activated lens can be placed in a solution containing the coating material, step 374. The solution may include a hydrophilic polymer solution as described and water. In some cases, the solution is pH>7. The solution can be agitated to create a well-stirred bath in which to incubate the lenses. In some cases, the lenses are incubated for about 50 minutes.

Second, the lens can be transferred to a water bath to equilibrate 376 in water. This equalization step can also be used to wash excess polymer from the lens. Lenses can be equilibrated in water for approximately 50 minutes. The lens can be transferred to a packaging container 378 with a packaging solution. Additionally, as an additional step, the lenses can be autoclaved. In some cases, the lenses are autoclaved at about 250°F for about 30 minutes. After this autoclaving step, the resulting coated lens is ready for use 382.

Advantageously, the methods described herein provide a cost-effective coating procedure that is comparable to contact lens manufacturing methods currently used in the industry integration.

Some specific examples of this method can be understood as a dipping method in which an activated lens core is immersed in a reaction solution including a hydrophilic macromonomer reactant in a stirred vessel, and the reaction vessel is operated to achieve appropriate reaction conditions. In terms of biochemical engineering, the aspect of reaction vessel and conditions can be understood as taking place in a continuously stirred reaction tank (CSTR). In a typical embodiment, the reaction step occurs in a reaction solution with an aqueous solvent. Such aqueous solvents may include one or more of water, methanol, ethanol, or any suitable aqueous solvent that dissolves PEG.

FIG. 11A provides a schematic diagram of a continuously stirred reaction tank (CSTR) 400 suitable for carrying out the reaction. The CSTR 400 includes an agitator 402 for agitating the reaction contents within the tank. Feed line or conduit 404 allows input or flow 406 of a reaction solution comprising a hydrophilic polymer solution containing at least one polymer species. As shown, the first and second polymer species flow into the CSTR 400 . In some cases, the first and second polymer species have different flow rates VP1 and VP2, respectively. In other cases, the flow rates may be the same.

FIG. 11A shows a plurality of contact lenses 404a and 404b in CSTR 400. In some cases, the contact lens can be held in a mesh holder with openings or sufficient porosity to enable contact between the held lens and the solution in the CSTR.

FIG. 11A also shows an output or outflow opening or conduit 408 for removing fluid from the CSTR 400 . In some cases, the removed fluid is a spent reaction fluid. The flow rate of this removed fluid may be referred to as V ₀ .

In some cases, _Tp represents the polymer residence time, and _Tc represents the contact residence time in the CSTR 400. Figure 11B shows polymer coating particle size as a function of time in CSTR 400 with _Tp ranging from 1-72 hours and _Tc ranging from 0.25-24 hours.

In some variations, in the reaction solution, the total hydrophilic macromonomer concentration in the solution is typically between about 0.01 (w/v)% and about 0.50 (w/v)%. In some embodiments, the first and second macromonomer subpopulation systems are present in the solution at substantially equal concentrations. However, in other embodiments, the concentration of reactive moieties (electron pair acceptors) of the second subpopulation of macromonomers exceeds the concentration of reactive moieties (nucleophiles) of the first subpopulation of macromonomers.

The excess of electrons to reactive moieties relative to nucleophilic reactive moieties may be beneficial for reactions included herein for the purpose of forming hydrogel-coated contact lenses in the electrons of the hydrophilic polymer subpopulation so functionalized There are two responses to the receptive moiety. Electron pair acceptor functionalized polymer subpopulations participate in (1) covalent crosslinking of the functionalized subpopulations with nucleophiles, and (2) covalent attachment to a polysiloxane-based core lens Nucleophilic sites on the surface. In contrast, the nucleophilic moiety functionalized polymer subpopulation only participates in a single reaction in which it participates in the electron pair accepting moiety functionalized polymer subpopulation.

Reactant concentrations can also be appropriately expressed in terms of the relative concentrations of the reactive moieties of the participating macromonomers rather than the concentrations of the macromonomers themselves. This may vary to the extent that the macromonomer system is decorated with functional moieties that actually participate in the reaction. Thus, in some reaction embodiments, the second macromonomer The concentration of the reactive moiety of the subpopulation exceeds the reactive moiety of the first macromonomer subpopulation by at least about 1%. In a more particular embodiment, the concentration of the reactive moiety of the second subpopulation of macromonomers exceeds the concentration of the reactive moiety of the first subpopulation of macromonomers by an amount between about 1% and about 30%. And in yet more particular embodiments, the concentration of the reactive moiety of the second subpopulation of macromonomers exceeds the concentration of the reactive moiety of the first subpopulation of macromonomers by an amount between about 5% and about 20%.

Returning now to the aspect of reaction conditions, in some embodiments, the reaction step is carried out for a period of between about 5 minutes and about 24 hours. In particular embodiments, the reacting step is carried out for a period of between about 0.5 hours and about 2 hours. In some embodiments, the reaction step is carried out at a temperature ranging between about 15°C and about 100°C. In a more particular embodiment, the reaction step is carried out at a temperature ranging between about 20°C and about 40°C. In some embodiments, the isoreaction step is performed at a pH between about 7 and about 11.

In some embodiments, the activated lens material is incubated in a diluted reaction solution containing 4-arm branched 10 kDa PEG end-functionalized with thiol groups and 8-arm branched 10 kDa PEG end-functionalized with vinyl thiol groups. The diluted solution contained between 0.01 and 0.5% total polymer, with a 10% excess of excess vinyl base. The reaction can be carried out under aqueous conditions, methanol, ethanol or other solvents in which PEG is soluble. The reaction can be carried out at a temperature ranging between about 15°C and about 100°C. The reaction can be carried out for between about 5 minutes and about 24 hours. The reaction can be carried out at basic pH, preferably in the range of 7-11.

Since the polymer reaction proceeds in dilute solution, a hydrogel (eg, crosslinked hydrophilic polymer particles) is formed when the branched polymers react with each other. The progress of the reaction can be monitored using dynamic light scattering techniques to measure hydrogel particle size and/or macromonomer aggregation levels as the hydrogel network is formed. Temperature, pH, convective velocity and concentration will affect the reaction rate and the hydrogel particle size and formation rate. Hydrogel particles smaller than visible light will not cause optical distortion in contact lenses. Layer thickness can be adjusted by monitoring hydrogel formation during the course of the reaction.

唑啉)及聚伸乙亞胺(PEI)、聚(丙烯酸)、聚甲基丙烯酸酯及其他丙烯酸系聚合物、聚電解質、玻尿酸、聚葡萄胺糖、聚葡糖。 In some variations, the polyethylene glycol is a hydrophilic polymer. However, other multifunctional natural and synthetic hydrophilic polymers can also be used, such as poly(vinyl alcohol), poly(vinylpyrrolidone), poly(N-isopropylacrylamide) (PNIPAM) and polypropylene amide Amine (PAM), Poly(2-

oxazoline) and polyethyleneimine (PEI), poly(acrylic acid), polymethacrylate and other acrylic polymers, polyelectrolyte, hyaluronic acid, polyglucosamine, polydextrose.

In other embodiments, the methods include the step of forming a layer of a crosslinked hydrophilic polymer on the lens surface that is covalently attached to the contact lens. Covalent linkages between branched hydrophilic polymers may occur due to Michael-type nucleophilic addition reactions between vinyl thiols and thiols, while covalent linkages between the hydrophilic polymers and the lens surface occur due to It occurs as a result of a conjugate addition reaction between the vinyl susceptor and the nucleophile produced during the activation step. In some cases, the reactivity of the nucleophile will increase with increasing pH as the molecule is progressively deprotonated.

In other variations, any general Michael-type reaction between an enol ester and a conjugated carbonyl can also be used. For example, acrylate , methacrylate or maleimide can replace vinyl. Other examples include Gilman's reagents, which are effective nucleophiles for addition to conjugated carbonyl groups. Stork enamine reactions can be performed using enamines and via conjugated carbonyl groups.

Other covalent reaction mechanisms include hydroxylamine reactions using nucleophiles such as aldehydes or ketones to create oxime linkages.

Other covalent reaction mechanisms include the reaction of N-hydroxysuccinimidyl esters with amines.

Other covalent reaction mechanisms include reaction with isocyanates of nucleophiles, including alcohols and amines, to form urethane linkages.

Other embodiments provide methods of forming contact lenses that include casting lenses in disposable soft molds. In some embodiments, the lenses are agar-coated. This can be done by encapsulating the lenses in agar solution. The agar is cooled and hardened. After hardening, the encapsulated lens is removed from the agar, resulting in a top piece that creates the concave side of the lens and a bottom piece that matches the convex side of the lens. The mold was disassembled and a first drop of liquid hydrogel solution was added to the lower half of the mold, followed by the activated lens core, followed by another drop of liquid hydrogel solution, followed by the upper half of the lens. The mold is then incubated until the hydrogel solidifies, and the contact lens is then removed from the mold to obtain a lens with an attached hydrophilic layer.

In some embodiments, a soft molding process using agar is used. For example, Delrin plates can be machined to have cavities (eg, 12 cavities). To make the mold, the agar can be melted and a small amount of liquid agar is added to the mold cavity, followed by the lens, and then additional liquid agar to cover the lens. The mold can be frozen to solidify the agar. In some cases, The mold can be frozen in the freezer for about 20 minutes to set the agar.

In other embodiments, the lens is punched around the lens using a punch having the same diameter as the lens. The top of the mold can then be removed using a small vacuum pick-up tool, and a second vacuum pick-up tool can then be used to move the lens out of the mold and replace the mold top.

This procedure can produce soft disposable mold plates with mold cavities that match the lenses to be coated (the lenses used to form these molds can be of the same type as those to be coated, but are not the actual lenses that are ultimately coated) .

To manufacture a coated lens, the lens core can be activated using one of the methods described above. The top of the agaric lens mold can then be removed and the hydrogel precursor solution (eg, 10 μL) added to the bottom of the mold, followed by the lens core, followed by more hydrogel precursor solution (eg, 10 μL), Next is the lid of the mold. Use tweezers to push down the top of the mold and remove any air bubbles.

The lens disk can then be incubated. In some cases, the lens disks were incubated at 37°C for 1 hour to polymerize the hydrogel. After polymerization, the lenses can be removed from the molds and stored in azide-containing PBS to prevent contamination.

To observe the layer thickness, a small amount of luciferin-maleimide can be added to the hydrogel layer on the coated lens. The luciferin-maleimide reacted covalently with the hydrogel and made the layer visible when using fluorescence microscopy.

In some cases, the coated lens can be held in parallel by impacting 2 to cut the lens and leave a thin section of the slice between the blades The blade cuts the original 500 micron thick section. Lens cross-sections can be visualized using fluorescence microscopy (this is for lenses functionalized with hydrogel on only one side, the uncoated side is used as an internal control). In some cases, the average thickness is estimated to be about 25 microns according to this technique.

In addition, soft agar molds can be used for coated polysiloxane hydrogel core lenses as well as coated pure polysiloxane cores. Lenses can also be evaluated using the contact angle measurement technique described or any other suitable technique.

In other embodiments, casting techniques can be used to attach the PEG-containing layer to the silicone-containing lens layer. First, the polysiloxane-containing layer is modified to ensure the presence of surface groups that will covalently react with the PEG macromonomer. Next, a mold is prepared containing a top portion and a bottom portion in the same or similar shape as the polysiloxane-containing layer. The polysiloxane-containing layer was placed into the mold along with the liquid macromonomer PEG solution, and the molds were then placed halfway together. The PEG can be thermally cured for about 1 hour, and the mold released.

The PEG-containing layer can also be attached to the polysiloxane-containing layer using dip coating. First, the polysiloxane-containing layer is modified to ensure the presence of surface groups that will covalently react with the PEG macromonomer. For example, surface groups can be created during a plasma treatment step, or by being in an alkaline solution or incubation, or by including reactive groups in the monomer mixture. Next, a dip coating solution prepared from a dilute solution of the reactive branched hydrophilic polymer was prepared. Activated lenses are placed in the dip coating solution and incubated for 1-24 hours. After incubation, the lenses were rinsed thoroughly and autoclaved in an excess volume of buffer solution prior to measuring the trapped bubble contact angle.

In an alternative approach, the hydrophilic polymer layer may use other The dip coating method is covalently attached to the polysiloxane-containing layer. First, the polysiloxane-containing layer can be modified to create surface chemical moieties that are covalently reactive with hydrophilic macromonomers. For example, surface groups can be created during a plasma treatment step, or by being in an alkaline solution or incubation, or by including reactive groups in the monomer mixture. Second, dip coating solutions prepared from dilute solutions of reactive branched hydrophilic polymers can be prepared. For example, the dilute solution may consist of branched poly(ethylene glycol) end-functionalized with vinyl and thiol groups in a solution containing 0.2 M triethanolamine. The activated lenses are placed in the dip coating solution and incubated at a temperature between about 20°C and about 60°C for 1-24 hours. Following incubation, the lenses were rinsed thoroughly and autoclaved in an excess volume of phosphate buffered saline.

In exemplary embodiments, the present invention provides methods of making the contact lenses described herein. The method includes contacting an activated lens with a dip coating solution to manufacture a contact lens. In an exemplary embodiment, the method additionally includes activating the lens, thereby producing an activated lens. Lenses can be activated via methods known to those skilled in the art or methods described herein, such as plasma treatment or incubation in alkaline solutions, or by including reactive groups in the monomer mixture. In exemplary embodiments, the contacting is performed for 1-24 hours, or 1-12 hours, or 12-24 hours, or 6-18 hours. In an exemplary embodiment, the method additionally includes rinsing the lens after the contacting step. In an exemplary embodiment, the method additionally includes autoclaving the lens after the contacting step. In an exemplary embodiment, the method additionally includes autoclaving the lens after the rinsing step.

In other embodiments, a replacement for contact lenses is formed The method includes a spray route in which reactive ultrasonic spray is used to coat a substrate with a thin adhesive layer of cross-linked hydrogel. Crosslinked films were fabricated using a two-component hydrogel comprising a branched PEG terminated with vinyl and a branched PEG terminated with thiol. The two components are simultaneously dropped onto an ultrasonic nozzle, where the components are mixed and atomized into small droplets, which are then accelerated to the substrate in the air envelope. The reaction rate is adjusted to ensure that the reaction is fast enough to form a solid structure on the surface, but low enough that the components do not polymerize immediately upon mixing at the nozzle.

An alternative spray method considered suitable for mass production is ultrasonic spraying, a technique that produces precise thin film coatings. It has previously been used in the stent and microelectronics industries, and is currently used in several mass production lines. Coated contact lens prototypes were formed using the latest technology from Sonotek instruments. The technology uses 3D printing, which may provide a platform for building complex lens structures with integrated sensors or electronics.

The Sonotek instrument has an ultrasonically driven nozzle with two feed lines that deposit the solution to the tip. The two-component hydrogel system consists of dissolving the PEG vinyl susceptor component in methanol containing triethanolamine ((TEOA; as organic substrate) and the PEG thiol component in pure methanol. A rate of 5 microliters was delivered to the tip of the nozzle, and the concentration of each PEG component was adjusted to mix equal volumes of the various components to obtain a 10% molar excess of vinyl siloxane. When the solution was deposited on the ultrasonic tip, They are mixed and atomized into droplets of about 20 microns in diameter. The droplets are then accelerated by a pressurized air blanket onto the surface to be coated. By including FITC-cis-butane in the PEG vinyl ash component enediimide, forming film deposition The mixing and cross-linking can be a film. Concentration of TEOA and confirmation that a TEOA:SH molar ratio of 6:1 can deposit uniform cross-linked hydrogels on a variety of substrates, including pure polysiloxane and polysiloxane hydrogel core lenses. A viable alternative to the water-based spray method was also tested and shown, however, for contact lens substrates, the methanol method advantageously produces a ~5 micron highly uniform film. Contact angle measurements on coated lenses confirmed the integrity of the deposited films.

Figures 12A and 12B depict other specific examples of the method of this technique pertaining to the manufacture of lenses having covalently attached two-sided hydrogel layers, wherein the hydrogel layer sides differ in composition or depth. In some instances, it may be advantageous to manufacture contact lenses that are asymmetric (convex side and concave side) in thickness or composition of the hydrogel coatings associated with the two surfaces, respectively. For example, it may be advantageous to form a thicker hydrogel layer on the concave (or posterior) lens surface than on the convex (or anterior) lens surface to retain a greater amount of tears against the cornea and prevent dryness symptoms.

12A shows a method of making a lens with a thicker hydrophilic layer on a concave surface 503 in which a lens core 500 containing a UV blocker is immersed in a polymer-coated non-mixed solution 502 and then exposed to UV light 504. UV light accelerates reactions between polymers and between polymers and surfaces. Light strikes the lens in a vector normal to the lens surface, directly on the concave side 503 and passing through the convex side 501 . The concave side 503 is exposed to a higher dose of UV light, while the convex side 501 receives a lower dose because of the UV blocker present in the lens. This asymmetric UV dose produces a layer of varying thickness. To obtain a completely independent variant in terms of layer thickness control, it is also possible to use light doses of varying intensity to illuminate from all sides.

FIG. 12B shows an alternative method of fabricating a thicker hydrogel layer on the concave surface 503 of the lens 500 . As shown, the convex surface 501 of the lens 500 is held in a vacuum chuck 506 while the concave surface 503 is exposed to the coating polymer 502. Vacuum suction pulls the aqueous solvent through the lens 500 while concentrating the coated polymer at the lens interface of the concave surface 503. After the desired layer thickness is achieved, the lens 500 is removed from the suction cup 506 . In some variations, the lens 500 is then placed in a well-mixed bath of coated polymer to continuously build up a hydrogel layer on both sides of the lens.

G. Examples

The present invention is further illustrated by the following examples. These examples are not intended to define or limit the scope of the invention.

Example 1: Functionalization of polysiloxane hydrogel lenses. The polysiloxane hydrogel [0001] lenses were stored in purified water prior to functionalization. A 10 vol % solution of divinyl group in .5M sodium bicarbonate (pH 11) was prepared. Lenses were added to the solution at a rate of 6 lenses per 10 mL of solution and mixed vigorously for 60 minutes on a shaker plate. The lenses were removed, rinsed in a filter to remove any excess reaction solution, and added to a container of purified water at a rate of 1 lens per 20 mL of water. They were mixed vigorously on a rocking plate for 60 minutes. The cleaning process was repeated two more times for a total of 3 cleanings. Next, the lenses were stored in triethanolamine (TEOA) for at least 20 minutes to a maximum of 6 hours before attaching the hydrogel layer.

Example 2: Functionalization of polysiloxane lenses. Silicone lenses were stored dry prior to functionalization. The ratio of 6 lenses per 10mL Add the lenses to a solution of 10% hydrochloric acid and 2% hydrogen peroxide. The lenses were mixed vigorously for 5 minutes and then removed, rinsed in a plastic filter to remove any excess reaction solution, and then added to a container of purified water at a rate of 1 lens per 20 mL of water. They were mixed vigorously for 5 minutes. Next, the lenses were added to a solution of 95% ethanol, 3% water, 1% glacial acetic acid, and 1% 3-mercaptopropyltrimethoxysilane and mixed vigorously for 60 minutes. The lenses were rinsed with pure ethanol in a filter and added to a container of pure ethanol at a rate of 1 lens per 20 mL of ethanol. The lenses were mixed vigorously for 60 minutes. The cleaning process is repeated one more time. The lenses are finally removed from the rinse solution and allowed to dry. They were stored at 4°C. Before attaching the hydrogels to the lenses, they were immersed in a 150 mM dithiothreitol solution for 30 minutes and then rinsed in DI water. After this step, the hydrogel must be attached within 15 minutes.

Example 3: Plasma functionalization of polysiloxane-containing layers. The polysiloxane-containing layer (polysiloxane or polysiloxane hydrogel) was placed in a vacuum chamber for 2 hours to ensure all moisture was removed. After drying, the lenses were inserted into the plasma chamber. The pressure was reduced to 375 milliTorr with a continuous flow of nitrogen at 10 standard cubic meters per minute. The chamber was allowed to settle for 30 seconds before starting the 100W plasma for 3 minutes. The chamber was then vented to the atmosphere and the lenses were removed. Then use the lenses within 1 hour.

Example 4: Preparation of a mold for adding an integral layer to a contact lens. The molds were prepared using silicone hydrogel lenses and agar. Dissolve 5 grams of agar in 333 mL of water and heat the solution on a temperature controlled stir plate until it reaches 88°C. Use a cavity containing a small cavity (1 inch diameter and .5 inches deep) Delrin board to accommodate each individual die. Use a straw to drip in liquid agar to fill the mold cavity to half full. The contact lenses were then placed convex side down on top of the molten agar and additional agar was added to the top to completely enclose each lens in the agar. Each plate contained 12 cavities and after all 12 were formed, the plate was placed at 4°C for 10 minutes until fully solidified. Once solid, a small brass punch with the same diameter (14 mm) as the contact lens was used to punch a hole in the agar around each lens. Use a hand-held vacuum cup to pull the top of the agar mold out, use tweezers to remove the silicone hydrogel lens, and replace the mold top. Do this procedure for each die. The molds are then ready for hydrogel attachment.

Example 5: Preparation of poly(ethylene glycol) hydrogel macromonomer solution. PEG hydrogels consist of two components. The first is an 8-arm 10 kDa poly(ethylene glycol) (PEG) (PEG-VS) end-functionalized with vinyl susceptors. The second is a 4-arm 10 kDa PEG end-functionalized with thiol groups (PEG-SH). PEG-VS was dissolved to 10% w/v in triethanolamine buffer (TEOA) at pH 8.0 and then filter sterilized in a 0.45 micron PVDF filter. PEG-SH was dissolved to 10% w/v in distilled water and then filter sterilized in a 0.45 micron PVDF filter.

Example 6: Fabrication of PEG hydrogels. To form the PEG hydrogel, the macromonomer solutions of Example 5 were mixed together. To achieve different polymer concentrations, a diluted volume of TEOA was added to the PEG-VS solution prior to mixing. The components were mixed together with a 10 mol% excess of thiol groups. The following table lists the quantities used to make various weight percent PEG hydrogels. For example, to form a 5% PEG hydrogel: 96 μL of TEOA was added to 30 μL of PEG-VS in an Eppendorf tube. Finally, 66 mL of PEG-SH was added to the tube and mixed using a vortex for 3 seconds to ensure complete mixing. The PEG hydrogel was then incubated at 37°C for 1 hour to ensure complete polymerization.

Example 7: Determination of non-swollen PEG hydrogel formulations. The hydrophobic PEG hydrogel macromonomer solution of Example 6 was pipetted between two glass slides separated by a 1 mm spacer and allowed to incubate at 37°C for 1 hour. To determine the swelling ratio, the PEG hydrogels were weighed immediately after polymerization and then immersed in distilled water for 24 hours. The swollen PEG hydrogel was weighed again to determine the amount of water absorbed into the polymer network to determine the combined mass gain. As can be seen below, the mass change of all PEG hydrogel formulations was small, and the 5% PEG hydrogel formulation did not experience any swelling after polymerization.

Example 8: Fabrication of a contact lens with a monolithic layer of PEG hydrogel on the concave side. To make contact lenses with monolithic layers of PEG hydrogels, the molds of Example 3 were prepared using the same sacrificial lenses that housed the monolithic layers of PEG hydrogel. A solution of 50 vol% TEOA, 34.4% PEG-SH, and 15.6% PEG-VS was prepared by mixing and vortexing in an Eppendorf tube. The top of the agar mold was removed using a small hand-held vacuum and a functionalized lens (the lens of Example 1 or Example 2 or Example 3) was placed into the mold. 20 [mu]L of the mixed PEG solution was placed on the concave side of the lens and the top of the agar mold top was displaced. Air bubbles were removed by tapping the top of the mold until all air was removed from the mold. The mold was placed in an incubator at 37°C for 1 hour. The lenses were then removed, visually inspected, and placed in purified water for storage.

Example 9: Fabrication of a contact lens with a monolithic layer of PEG hydrogel on the convex side. To make contact lenses with monolithic layers of PEG hydrogels, the molds of Example 3 were prepared using the same sacrificial lenses that housed the monolithic layers of PEG hydrogel. A solution of 50 vol% TEOA, 34.4% PEG-SH, and 15.6% PEG-VS was prepared by mixing and vortexing in an Eppendorf tube. Use a small hand-held vacuum to move The top of the agar mold was removed and 20 μL of the mixed polyethylene glycol solution was placed in the bottom of the mold. A functionalized lens (the lens of Example 1 or Example 2 or Example 3) was placed on top of the mold, and the top of the agar mold top was displaced. Air bubbles were removed by tapping the top of the mold until all air was removed from the mold. The mold was placed in an incubator at 37°C for 1 hour. The lenses were then removed, visually inspected, and placed in purified water for storage.

Example 10: Production of a contact lens with a monolithic layer of hydrogel (encapsulated) on both the concave and convex sides. To make contact lenses encapsulated in a monolithic layer of PEG hydrogel, the mold of Example 4 was prepared using the same sacrificial lens as the lens housing the monolithic layer of PEG hydrogel. A solution of 50 vol% TEOA, 34.4% PEG-SH, and 15.6% PEG-VS was prepared by mixing and vortexing in an Eppendorf tube. The top of the agar mold was removed using a small hand-held vacuum and 20 μL of the mixed polyethylene glycol solution was placed in the bottom of the mold. A functionalized lens (lens of Example 1 or Example 2 or Example 3) was placed into the mold and 20 μL of the mixed PEG solution was placed on the concave side of the lens, then the top of the agar mold was placed on top . Air bubbles were removed by tapping the top of the mold until all air was removed from the mold. The mold was placed in an incubator at 37°C for 1 hour. The lenses were then removed, visually inspected, and placed in purified water for storage.

Example 11: Oaysys lenses encapsulated in PEG hydrogels. Contact lenses (Acuvue Oaysys, Letrofecon A) were functionalized according to Example 1 . The agar molds were prepared according to Example 4. Lenses were encapsulated according to Example 10.

Example 12: Oaysys with PEG hydrogel monolithic layer lens. Contact lenses (Acuvue Oaysys, Lotrifilcon A) were functionalized according to Example 1 . The agar molds were prepared according to Example 4. The monolithic layer was prepared according to Example 8.

Example 13: PureVision lenses encapsulated in PEG hydrogels. [0002]

Contact lenses (PureVision, Palafecon A) were functionalized according to Example 1 . The agar molds were prepared according to Example 4. Lenses were encapsulated according to Example 10.

Example 14: PureVision Lens with PEG Hydrogel Monolithic Layer. [0003]

Contact lenses (PureVision, Palafecon A) were functionalized according to Example 1 . The agar molds were prepared according to Example 4. The monolithic layer was prepared according to Example 8.

Example 15: Silicone lens encapsulated in a monolithic layer of PEG hydrogel. Silicone lenses (NuSil, Med 6755) were functionalized according to Example 2. The agar molds were prepared according to Example 4. Lenses were encapsulated according to Example 10.

Example 16: Silicone lens with a monolithic layer of PEG hydrogel on the concave side. Silicone lenses (NuSil, Med 6755) were functionalized according to Example 2. The agar molds were prepared according to Example 4. The monolithic layer was prepared according to Example 8.

Example 17: Silicone lens with monolithic layer of PEG hydrogel on convex side. Silicone lenses (NuSil, Med 6755) were functionalized according to Example 2. The agar molds were prepared according to Example 4. The overall layer is based on Example 9 was prepared.

Example 18: Contact angle measurements. To measure the contact angle, the trapped bubble technique was used. First, swirl the lens in distilled water to remove surface contamination. The lens is then immersed in distilled water and suspended on top of a plate with holes through which the convex surface of the lens protrudes downward. A 11/16 inch diameter stainless steel ball was placed on top of the lens to hold it in place when the bubble was applied. Next, place the curved tip of a 16 gauge blunt needle under the surface in the center of the lens. The bubble is then advanced until it contacts the lens, at which point the bubble is withdrawn until it bursts out of the lens or needle. A high-definition video camera records the complete process and then stores the frame from the moment before the bubble detaches from the lens or the needle. From the image, the angle between the lens and both sides of the bubble was calculated in MATLAB and stored as the contact angle of the lens.

Example 19: Contact angle measurements of Oasys lenses with PEG hydrogel monolithic layers. The contact angle of the lens of Example 11 was measured according to Example 18.

Example 20: Preparation of photopolymerizable poly(ethylene glycol) hydrogels Gum Monomer Solution. The hydrogel consists of two components. The first is an 8-arm 10 kDa poly(ethylene glycol) (PEG) (PEG-Ac) end-functionalized with acrylate. The second is a 4-arm 10 kDa PEG end-functionalized with thiol groups (PEG-SH). PEG-Ac was dissolved to 10% w/v in triethanolamine buffer (TEOA) pH 8.0, then filter sterilized in a 0.45 micron PVDF filter. PEG-SH was dissolved to 10% w/v in distilled water and then filter sterilized in a 0.45 micron PVDF filter.

Example 21: Fabrication of photopolymerizable PEG hydrogels. To form the hydrogel, the macromonomer solutions of Example 20 were mixed together. To achieve different polymer concentrations, a diluted volume of TEOA was added to the PEG-Ac solution prior to mixing. The components were mixed together with a 10 mol% excess of thiol groups. The following table lists the amounts used to make different weight percentages of hydrogels. For example, to form a 5% PEG hydrogel: add 96 μL of TEOA to 30 μL of PEG-Ac in an Eppendorf tube. Finally, 66 mL of PEG-SH was added to the tube and mixed using a vortex for 3 seconds to ensure complete mixing. The solution was then exposed to UV light (365 nm, 5 mW/cm2, 10 min) to polymerize the mixture.

Example 22: Layer-by-layer reactive spin coating. The macromonomer solution of Example 20 was prepared. The lens of Example 1 or 2 or Example 3 was secured to the spin coater chuck. The lenses were rotated at a speed of 500-5000 rpm. While rotating, the lens was continuously exposed to UV light (365 nm, 5 mW/cm2) while the macromonomer solution was added staggered to the lens as follows: 10 μL of PEG-Ac followed by 10 μL of PEG-SH, etc. This is repeated for a number of cycles, from 10-1000 cycles.

Example 23: PEG Impregnation Solution for Enzyme-Mediated Redox Chain Initiation. The PEG impregnation solution consisted of a mixture of glucose oxidase (GOX), Fe+2 and polyethylene diacrylate (PEGDA) (MW 2,000Da-10,000Da). For example, the impregnation solution may contain 3.1 x 10-6M GOX, 2.5 x 10-4M iron(II) sulfate, 10% PEGDA 5,000 Da.

Example 24: Redox chain priming mediated by interfacial enzymes Contact lenses encapsulated in PEG hydrogels. The glucose-loaded lens of Example 18 was dipped into the solution of Example 19 until the hydrogel layer grew to the desired thickness. The time to achieve a layer thickness of 10-100 microns is 2 seconds to 10 minutes.

Example 25: Trapped bubble contact angle measurement. A 10x macro lens was mounted on the camera detailed in Example 17 for Contact Angle Measurements. This macro lens enables close-up video of the bubble/contact lens interface. A syringe pump (New Era Syringe Pump 750) was added to the test fixture to enable continuous and repeatable bubble control. Use the Syringe Pump Pro planning software to plan the pump's work schedule. A new test fixture chamber of black acrylonitrile butadiene styrene (abs) was constructed to facilitate the use of thin, clear glass viewing plates and translucent background screens. The test lens was held between two plates and submerged in PBS. The air bubble extends 2mm from a straight 16 gauge blunt needle until it contacts the lens. The lens+bubble interface was recorded by a high definition webcam when 3 μl of air was injected and then pulled away from the microsyringe (Precision Sampling corp, series A-2, 25ul) at a rate of 7.2 μl/min. The contact angles of the lenses described herein were measured using Example 25 and are detailed in Figures 13A-13T. Contact angles were measured using the specially developed MatLab Code detailed in Figures 14A-14J.

Example 26: PEG concentration dependence. To determine the effect of PEG concentration on the rate of hydrogel polymerization, the macromonomer solution of Example 4 was combined at decreasing concentrations and checked at set time intervals until solidification. PEG-VS and PEG-SH were combined with the indicated amounts of .2M TEOA in the following amounts in 1.5ml Eppendorf tubes. Each solution was vortexed, and then Then transfer to a glass slide with a pipette. The PEG solution was pipetted at 5, 10 or 30 second intervals (increasing time intervals for lower concentrations) until filaments formed, indicating that the gel had polymerized. Record the time until aggregation.

Example 27: pH dependence of PEG. To determine the rate of polymerization of hydrogels as a function of pH, the macromonomer solution of Example 4 was combined with increasing pH levels of .2M TEOA. 20% PEG-VS and 10% PEG-SH were combined with TEOA at the indicated pH in 1.5 ml Eppendorf tubes. The TEOA buffers were prepared at the noted concentrations and by adjusting the pH with NaOH or HCl as needed. A 4% hydrogel solution was made. Each solution was vortexed and pipetted onto a glass slide. The PEG solution was pipetted at 5, 10 or 30 second intervals (increasing time intervals for lower pH) until filaments formed, indicating that the gel had polymerized. Record the time until aggregation.

Example 28: Dip coating to obtain lenses of PEG monolithic layers. The lens is in plasma set at 375mTorr, 3min, 100% RF power Functionalized using nitrogen in a chamber (Plasma Etch PE-50). The pressure was reduced to 375 milliTorr with a continuous flow of nitrogen at 10-20 standard cubic meters per minute. The chamber was allowed to settle for 30 seconds before starting the 100W plasma for 3 minutes. The chamber was then vented to the atmosphere and the lenses were removed. Then use the lenses within 1 hour. The PEG macromonomer solution of Example 4 was combined with excess TEOA to obtain solutions with total solids concentrations of .1% and .5% with a 10% molar excess of VS (see quantities in the table below). A 0% PEG solution was also prepared as a control. The volume of .2M TEOA detailed below was added to individual plastic vials (McMaster Carr 4242T83); followed by the noted volume of PEG-VS. Surface-functionalized PureVision lenses were added to the solution and vortexed. PEG-SH was added and the solution was vortexed again. The lenses were placed on the mixing table for 24 hours. The lenses were transferred to new plastic vials containing Phosphate Buffered Saline (PBS) and placed on a mixing table for 24 hours. Lenses were transferred to glass jars and autoclaved (Tuttnauer 3870 E) at 250°F for 30 minutes on a wet cycle.

Example 29: Polysiloxane lens surface activated to enhance hydrogel adhesion. Silicone lenses (NuSil, Med 6755) were functionalized with the plasma treatment procedure of Example 28. In a 50mL conical tube, place the lens in 10% w/v divinyl susceptor with sodium bicarbonate buffer at pH 11 and vortexed. After 1 hour on the mixing station, the lenses were rinsed with 20 ml of deionized water (DI water) and placed back into 40 ml of DI water on the mixing station. After 1 hour, the cycle was repeated one more time and the lenses were placed in a refrigerator in 40 ml of DI water for 8 hours.

Example 30: Dip coating to obtain a polysiloxane lens with a PEG monolithic layer. Silicone lenses (NuSil, Med 6755) were functionalized in 0%, .1% and .5% PEG solutions according to Example 28, dip coated and autoclaved.

Example 31: PureVision lens surface activated and dip coated to obtain an integral PEG layer. Contact lenses (PureVision, Palafecon A) were functionalized with the plasma treatment procedure of Example 28. The lenses were placed in 400 uL of 10% PEGVS, vortexed, and then positioned on the mixing table for 5 minutes. Subsequently, the lenses were placed in 3 mL of .2M TEOA, vortexed, and placed on a mixing table for 5 minutes. The lenses were added to a solution of .1% PEG in TEOA according to Example 28. The lenses were vortexed, placed on a mixing table for 24 hours, and autoclaved according to Example 28.

Example 32: PureVision lenses dip-coated and added with FITC-maleimide to make the PEG layer visible. Contact lenses (PureVision, Palafecon A) were functionalized with the plasma treatment procedure of Example 28. The lenses were placed in 0.1% and 0.5% PEG solutions according to Example 28. 5.1 μl of FITC-maleimide at 10 mg/mL was added to each solution to make the PEG layer visible. Vortex the solutions and Place on mixing table for 24 hours.

Example 33: Dip Coating and Shortening Wash Cycles to Obtain PureVision Lenses with PEG Monolithic Layers. Contact lenses (PureVision, Palafecon A) were functionalized and coated according to Example 28. After 24 hours in the PEG solution, the lenses were placed in vials containing PBS and placed on a mixing table for 1.5 hours. The lenses were placed in a second set of vials containing PBS and placed on a mixing station for 1.5 hours. The lenses were autoclaved according to Example 28.

Example 34: PureVision Lenses Dip Coated in Ultra Low Concentration PEG with No Wash Cycle. Contact lenses (PureVision, Palafecon A) were functionalized with the plasma treatment procedure of Example 28. The macromonomer solution of Example 4 was combined with TEOA in .01% and .05% PEG. A 0% PEG solution was also prepared as a control. The PureVision lenses were added to the solution and vortexed. PEG-SH was added and the solution was vortexed again. The lenses were autoclaved at 250°F in individual plastic vials but not washed and not removed from the PEG solution.

Example 35: PureVision lenses dip-coated in low concentration PEG and autoclaved directly in glass. Contact lenses (PureVision, Palafecon A) were functionalized and coated according to Example 28. The lenses were placed in glass vials (McMaster- Carr 4417T48) and autoclaved according to Example 28.

Example 36: PureVision lenses dip-coated and extracted in isopropanol. Contact lenses (PureVision, Palafecon A) were functionalized according to Example 28 and coated at 0% and 0.5% concentrations. The lenses were placed on the mixing table for 18 hours. The PEG solution was replaced with pure isopropanol (IPA) and returned to the mixing station for 1 hour. The IPA was shaken and the lenses were washed for an additional hour. The IPA was replaced with deionized water, and the lenses were rinsed for 1 hour. The water was replaced twice, each cleaning the lenses for 30 minutes. The lenses were placed in PBS and autoclaved according to Example 28.

Example 37: PureVision Lenses Dip Coated in Organic Solvents to Obtain PEG Monolithic Layers. 1 ml of neat TEOA was added to 40 ml of isopropanol (IPA) to make a .2M solution. Pure methanol was added to .2M TEOA in IPA to yield a 50% solution. 1 ml of concentrated TEOA was dissolved in 40 ml of neat methanol (MeOH) to form a 0.2 molar solution of TEOA in MeOH. Contact lenses (PureVision, Palafecon A) were functionalized with the plasma treatment procedure of Example 28. The macromonomer solution of Example 4 was combined with the 50% MeOH and 50% IPA with .2M TEOA with 0.5% PEG. A 0% PEG solution was also prepared as a control. The macromonomer solution of Example 4 was also combined with the MeOH with 0.2M TEOA (with .5% PEG). The volumes of MeOH and IPA detailed below were added to individual plastic vials; surface functionalized PureVision lenses were added to the solution and vortexed. PEG-VS and PEG-SH were added to the solution, but the solution was not swirled due to the sensitivity of the lenses in solvents. The lenses were placed on the mixing table for 18 hours. Use a cleaning series to remove the The organic solvent was equilibrated; the solution was changed to pure IPA and the lens was placed on the mixing table for 1 hour. The IPA was replaced with deionized (DI) water and the lenses were placed on a mixing table for 1 hour. The DI water was replaced with PBS and the lenses were autoclaved according to Example 28.

Example 38: PureVision lenses activated by DVS during IPA solvent extraction. 1 ml of 100% TEOA was added to 40 ml of isopropanol (IPA) to make a .2M solution. Contact lenses (PureVision, Palafecon A) were functionalized according to Example 28 and placed in 5 ml of IPA of .2M TEOA. Unplasma treated and non-PEG lenses were also prepared as controls. 7.5% DVS was added to each vial. The lenses were swirled in the solution and then placed on the mixing table for 1 hour. The DVS was discarded and 40 ml of IPA was added to each solution before placing the lenses on the mixing table for 1 hour. The IPA was replaced and the lenses were placed on the mixing table for 1 hour. The IPA was replaced with 40 ml of deionized (DI) water and mixed for 1 hour. The DI water was replaced and the lenses were mixed for 1 hour. The lenses were dip coated and autoclaved according to Example 28.

Example 39: PureVision lenses activated by DVS during MeOH solvent extraction. 1 ml of 100% TEOA was added to 40 ml of methanol (MeOH) to make a .2M solution. Contact lenses (PureVision, Palafecon A) were functionalized according to Example 28 and placed in 5 ml of .2M TEOA in MeOH. Unplasma treated and non-PEG lenses were also prepared as controls. 7.5% DVS was added to each vial. The lenses were swirled in the solution and then placed on the mixing table for 1 hour. Discard the DVS and place the lenses on the mixing table for 1 hour 40 ml of IPA was added to each solution. The IPA was replaced and the lenses were placed on the mixing table for 1 hour. The IPA was replaced with 40 ml of deionized (DI) water and mixed for 1 hour. The DI water was replaced and the lenses were mixed for 1 hour. The lenses were dip coated and autoclaved according to Example 28.

Example 40: PureVision Lenses Dip Coated in Methanol Solvent to Obtain PEG Monolithic Layers. Contact lenses (PureVision, Palafecon A) were functionalized according to Example 28. A 0.2 molar solution of TEOA in MeOH was prepared according to Example 39. The macromonomer solution of Example 4 was also combined with the MeOH with 0.2M TEOA (with .1%, .25% and .5% PEG). A 0% PEG solution was also prepared as a control. The volumes of MeOH detailed below were added to individual glass vials; followed by the noted volumes of PEG-VS. Surface-functionalized PureVision lenses were added to the solution and vortexed. PEG-SH was added and the solution was vortexed again. The lenses were placed on the mixing table for 24 hours.

A MeOH wash cycle was developed and implemented: 0.2M TEOA in MeOH and PEG solution was replaced with pure MeOH and the lenses were placed on a mixing table for 1 hour. The MeOH was replaced with IPA and the lenses were placed on the mixing table for 1 hour. The IPA was replaced with a solution consisting of 50% IPA and 50% DI water and the lenses were placed on a mixing table for 1 hour. The 50% solution was replaced with 100% DI water and the lenses were placed on the mixing table for 1 hour. The DI water was replaced with phosphate buffered saline (PBS) and autoclaved according to Example 28.

Example 41: Plasma Treatment Procedure. Test and update the plasma handler settings. The plasma treatment procedure was performed using nitrogen in a plasma chamber (Plasma Etch PE-50) with the following settings, stage 5: 150 mTorr setting, 200 mtorr vacuum, 3 minutes at 100% RF power. The pressure was reduced to 200 milliTorr with a continuous flow of nitrogen at 2.5-5 standard cubic meters per minute. The chamber was allowed to settle for 30 seconds before starting the 100W plasma for 3 minutes. The chamber was then vented to the atmosphere and the lenses were removed. Then use the lenses within 1 hour.

Example 42: Lenses extracted, dried and dip coated in isopropanol. The lenses were placed in 1.5 ml of IPA and placed on the mixing table for 18 hours. The IPA was shaken and the lenses were washed for an additional hour. The IPA was replaced with deionized water, and the lenses were rinsed for 1 hour. The water was replaced twice, each cleaning the lenses for 30 minutes. The lenses were placed in a vacuum chamber and the chamber was evacuated using a pump (Mastercool, 6 cfm) for 24 hours. The lenses were functionalized according to Example 28 and coated at 0% and 0.5% concentrations and subjected to the plasma treatment procedure of Example 41. The PEG solution was replaced with deionized water, and the lenses were rinsed for 1 hour. The lenses were placed in PBS and autoclaved according to Example 28.

Example 43: Dip Coating to Obtain a PEG Monolithic Layer PureVision lenses. Example 28 was repeated using the plasma treatment procedure of Example 41.

Example 44: PureVision lenses dip-coated in low concentration PEG and autoclaved directly in glass. Example 36 was repeated using the plasma treatment procedure of Example 41.

Example 45: PureVision Lenses Dip Coated in Organic Solvents to Obtain PEG Monolithic Layers. Example 38 was repeated using the plasma treatment procedure of Example 41.

Example 46: PureVision Lenses Dip Coated in Methanol Solvent to Obtain PEG Monolithic Layers. Example 40 was repeated using the plasma treatment procedure of Example 41.

Example 47: PureVision lenses extracted in isopropanol, dried and dip coated and directly autoclaved. Contact lenses (PureVision, Balafec A) were extracted, dried and dip coated according to Example 42. The lenses were autoclaved according to Example 28 immediately after the dip coating procedure while in the PEG solution.

Example 48: Polysiloxane lenses extracted, dried and dip-coated in isopropanol. Silicone contact lenses (NuSil, Med 6755) were extracted according to Example 42, dried, dip coated and autoclaved.

Example 49: PureVision lenses extracted, dried and dip coated in isopropanol. Contact lenses (PureVision, Palafecon A) were extracted according to Example 42, dried, dip coated and autoclaved.

Example 50: PureVision Lenses of PEG Monolithic Layers Dip Coated in Methanol Solvent and Spin with Heat. contact lenses (PureVision, Palafecon A) was functionalized with oxygen in a plasma chamber (Plasma Etch PE-50) set at 200 mTorr, 3 min, 100% RF power. The lenses were dip coated according to Example 40 and spun in a heated oven at 37°C for 24 hours. The lenses were cleaned and autoclaved according to Example 40, but using the following reduced cleaning times: MeOH 2 times, swirling quickly; IPA 2 times, 20 minutes; IPA: H20 (50:50), 20 minutes; H20 , 10 min; and PBS for autoclaving.

Example 51: Dip-coating in methanol solvent and heating and spinning to obtain a polysiloxane lens with a PEG monolithic layer. Polysiloxane contact lenses (NuSil, Med 6755) were functionalized using oxygen in a plasma chamber (Plasma Etch PE-50) set at 200 mTorr, 3 min, 100% RF power. The lenses were dip coated according to Example 40 and spun in a heated oven at 37°C for 24 hours. The lenses were cleaned and autoclaved according to Example 40, but using the following reduced cleaning times: MeOH 2 times, swirling quickly; IPA 2 times, 20 minutes; IPA: H20 (50:50), 20 minutes; H20 , 10 min; and PBS for autoclaving.

Example 52: Preactivated PureVision lenses dip-coated in methanol solution and heated and spun. Lenses (PureVision, Balafec A) were functionalized using oxygen in a plasma chamber (Plasma Etch PE-50) set at 200 mTorr, 3 min, 100% RF power. The lenses were preactivated with PEG-VS or VS, dip coated according to Example 40, and spun in a heated oven at 37°C for 24 hours. The lenses were cleaned and autoclaved according to Example 40, but using the following reduced cleaning times: MeOH 2 times, swirling quickly; IPA 2 times, 20 minutes; IPA: H20 (50 : 50), 20 min; H20, 10 min; and PBS for autoclaving.

Example 53: Dip coating to obtain a polysiloxane lens with a PEG monolithic layer. Example 30 was repeated using the plasma treatment procedure of Example 41.

Example 54: PureVision Lenses Using Oxygen Dip Coating to Obtain PEG Monolithic Layers. Example 28 was repeated using oxygen during the plasma treatment procedure, stage 5.

Example 55: PureVision lenses plasma treated and dip coated in hyaluronic acid to obtain integral layers. Contact lenses (PureVision, Palafecon A) were functionalized according to Example 28 and the added hyaluronic acid (HA) was 10 mg of hyaluronic acid (HA). Lenses were added to the solution and placed on the mixing table for 1 hour. The HA solution was replaced with DI water and the lenses were placed on the mixing table for 1 hour. The water was replaced and the lenses were placed on the mixing table for 1 hour for 2 additional runs. The lenses were placed in individual plastic vials containing 3ml-5ml of PBS.

Example 56: PureVision lenses plasma treated and DVS surface activated in NaOH. Contact lenses (PureVision, Palafecon A) were functionalized according to Example 28. 0.5 ml of DVS was added to 4.5 ml of 0.5M sodium bicarbonate (NaOH). Lenses were added to this solution and placed on the mixing table for 20 minutes. Lenses were also placed in 5 ml of NaOH as a control. The solution was replaced with DI water and the lenses were placed on the mixing table for 20 minutes. This step was repeated 2 more times.

Example 57: Plasma treatment and dip coating in hyaluronic acid to obtain a monolithic layer and addition with FITC-maleimide to make the layer visible PureVision lenses. Contact lenses (PureVision, Palafecon A) were functionalized according to Example 28 and dip coated according to Example 55. 51 μl of FITC-maleimide was added to each solution to make the PEG layer visible. The lenses were cleaned according to Example 55 and stored.

Example 58: PureVision lenses plasma treated and dip coated in hyaluronic acid in NaOH to obtain integral layers. Contact lenses (PureVision, Palafecon A) were functionalized according to Example 28. 5ml of HA was added to 45ml of 10M NaOH. 5ml of HA was added to 45ml of DI water as a control. Lenses were added to these solutions and placed on the mixing table for 1 hour. The solutions were replaced with DI water and the lenses were placed on the mixing table for 1 hour. The lenses were placed in individual plastic vials containing 3ml-5ml of PBS.

Example 59: Polysiloxane lenses plasma treated and then encapsulated in PEG hydrogel. Silicone lenses (NuSil, Med 6755) were functionalized according to Example 28. The agar molds were prepared according to Example 4. Lenses were encapsulated according to Example 10.

Example 60: PureVision lenses plasma treated and dip coated in low or high molecular weight PEG. Contact lenses (PureVision, Palafecon A) were functionalized using polyfunctional polyethylene glycol (mPEG-VS) end-functionalized with vinyl. 5kDa and 20kDa mPEG were used.

A 5% w/v total mPEG-VS solution was prepared in triethanolamine buffer (TEOA) at pH 8.0 and then filter sterilized in a 0.45 micron PVDF filter. A 0% PEG solution was also prepared as a control.

Add 3ml of PEG solution to individual plastic vials (McMaster Carr 4242T83). Surface-functionalized PureVision lenses were added to the solution and vortexed. The lenses were placed on the mixing table for 24 hours. The lenses were transferred to new plastic vials containing Phosphate Buffered Saline (PBS) and placed on a mixing table for 24 hours.

Example 61: Polysiloxane lenses plasma treated and then encapsulated in PEG hydrogel with FITC-maleimide addition to make the PEG layer visible. Silicone lenses (NuSil, Med 6755) were functionalized according to Example 28. The agar molds were prepared according to Example 4. 5.1 μl of FITC-maleimide was added to each solution to make the PEG layer visible. Lenses were encapsulated according to Example 10.

Example 62: Oaysys lenses dried and plasma treated then encapsulated in PEG hydrogel. Contact lenses (Acuvue Oaysys, Xenoficon A) were dried according to Example 42 and functionalized according to Example 28. The agar molds were prepared according to Example 4. Lenses were encapsulated according to Example 10.

Example 62: Lenses encapsulated in PEG hydrogels. Lenses (Letrofecon B) were functionalized according to Example 1 . The agar molds were prepared according to Example 4. Lenses were encapsulated according to Example 10.

Example 63: Lenses dried and plasma treated then encapsulated in PEG hydrogels. Lenses (Letrofecon B) were dried according to Example 42 and functionalized according to Example 28. The agar molds were prepared according to Example 4. Lenses were encapsulated according to Example 10.

Example 64: Polysiloxane lenses plasma treated and dip coated in low or high molecular weight PEG. Silicone lenses (NuSil, Med 6755) was functionalized according to Example 28, with the addition of a control without plasma treatment, and dip coated according to Example 60.

Example 65: PureVision lenses plasma treated and then encapsulated in PEG hydrogel. Contact lenses (PureVision, Palafecon A) were functionalized according to Example 28. The agar molds were prepared according to Example 4. Lenses were encapsulated according to Example 10.

Example 66: PureVision Lenses Dip Coated to Obtain PEG Monolithic Layers. Contact lenses (PureVision, Palafecon A) were functionalized and coated according to Example 28. The lenses were cleaned according to Example 33 and autoclaved according to Example 28.

Example 67: Glucose loading of hydrogel contact lenses. Hydrogel contact lenses containing acrylate groups on the surface were incubated in d-glucose solution (10 mL/lens) for at least 4 hours. The glucose concentration can be from .1 mM to 25 mM.

Example 68: PureVision lens dipped and subjected to accelerated lifetime testing to confirm the stability of the bulk layer of PEG. Example 46 was repeated; contact lenses (PureVision, Palafecon A) were dip-coated in methanol solvent to obtain a monolithic layer of PEG. Following the autoclaving procedure according to Example 28, the lenses were tested according to Example 25. The lenses were placed in PBS and autoclaved once more according to Example 28, or in sterile saline (Walgreens-Sterile Saline Solution). The lenses were placed in a compounding oven (Stovall Life Science Inc) at 20, 40 or 60°C. These series of tests correspond to FDA 510K clearances for 6 to 12 months as medical devices in general (and especially for daily wear contact lenses) The date on which the Accelerated Use Period is required to be described in detail. After testing, the sterile saline was replaced with fresh sterile saline, and the lenses in the individual mixing ovens were replaced. Lot numbers corresponding to solutions and temperatures are detailed below.

Example 69: Dip coating to obtain MJS lenses of PEG monolithic layer. MJS lenses (MJS Lens Technology Ltd, standard product, 55% water content) were functionalized according to Example 41, coated and autoclaved according to Example 28, and tested according to Example 25. The lenses were then placed in a mixing oven (Stovall Life Science Inc) at 60°C for 7 days. Should Sterile saline (Walgreens-Sterile Saline Solution) was replaced and tested according to Example 25.

Example 70: Determination of water content of poly(ethylene glycol) coated contact lenses using mass balance. This example illustrates how to determine the water content of the contact lenses of the present invention. In work to determine the possible water content of the polyethylene glycol layers of the contact lenses of the present invention, samples consisting of the layer components were prepared for evaluation. The resulting gel was then hydrated and tested to determine water content.

The hydrophobic PEG hydrogel macromonomer solution described in Example 5 was pipetted between two glass slides separated by a 1 mm spacer and allowed to incubate at 37°C for 1 hour.

The hydrated samples were wiped dry and the mass in the hydrated state was recorded via mass balance. After recording the mass in the hydrated state, the samples were all dried overnight under a vacuum of <1 inch Hg.

[0004] The dried samples were removed from the vacuum oven after drying overnight and then measured to record the dry mass. Calculate the water content using the following relationship: water content = [(wet mass - dry mass)/wet mass] x 100%

Example 71: Preparation of a poly(ethylene glycol) hydrogel macromonomer solution. In one example, the PEG hydrogel consists of two components. The first is an 8-arm 10 kDa poly(ethylene glycol) (PEG) (PEG-VS) end-functionalized with vinyl susceptors. The second is a 4-arm 10 kDa PEG end-functionalized with thiol groups (PEG-SH). PEG-VS was dissolved to 10% w/v in triethanolamine buffer (TEOA) at pH 8.0 and then filter sterilized in a 0.45 micron PVDF filter. PEG-SH was dissolved to 10% w/v in distilled water and then filter sterilized in a 0.45 micron PVDF filter.

Example 72: Contact Lenses. In another example, the following lenses and materials were each processed by the following examples: Polysiloxane (NuSil, Med 6755); PureVision, Palaficon A; Acuvue Oaysys, Xenofecon A; AIR OPTIX, Letrofecon B. MJS Lens, MJS Lens Technology Ltd. All subsequent references to "lenses" include each of the foregoing lenses and materials.

Example 73: Dip-coated contact lenses to obtain monolithic layers of poly(ethylene glycol) (PEG) hydrogels. In other examples, commercially available and hydrated lenses were rinsed three times in deionized water for 30 minutes each. The lenses were dried in a vacuum chamber for 2-24 hours.

The lens surfaces were functionalized using nitrogen gas in a standard plasma chamber (Plasma etch PE-50) set at 200 mTorr, 3 min, 100 W RF power, 5-20 standard cubic meters per minute. Then use the lenses within 1 hour.

The PEG macromonomer system was combined with deionized water (DI water), isopropanol (IPA) or 0.2M TEOA in methanol (MeOH) to obtain solutions with total solids concentrations of .1%, .25% and .5%. Various concentrations of substrates were used: each solution was a 10% molar excess of VS (see quantities in the table below), and a 0% PEG solution was also prepared as a control.

The volumes of substrate detailed below were added to individual vials, followed by the noted volumes of PEG-VS. The surface functionalized lens was added to the solution. PEG-SH was added and the lenses were placed on the mixing table for 1 hour to 24 hours. The lenses were individually cleaned in the corresponding substrates for 30 minutes. For solvent conditions, a continuous 30-minute cleaning system is 100% IPA, 50% TA in DI water and 100% DI water. Lenses in aqueous substrates are only cleaned in 100% DI water.

The lenses were placed in phosphate buffered saline (PBS) and autoclaved at 250°F for 30 minutes in a wet cycle. Lens general comfort and contact angle were determined by wearing and direct in-house measurements, respectively.

Example 74: Dip-Coated Lenses with Recycled PEG. In other examples, the steps of Example 73 above were repeated for contact lenses PureVision (Palafecon A) at a TEOA concentration of 0.4M. PEGs from this program are preserved. After 24 hours, a PEG solution was developed using 50% original (750 μL) and 50% fresh or non-previously used PEG. Example 73 was repeated using this PEG solution.

Example 75: Activation of lens surfaces using hydrogen peroxide and dip coating. In other examples, the dehydrated contact lenses PureVision (Palafecon A) were placed in commercially available hydrogen peroxide for 1 hour. The lenses were rinsed with DI water for 30 minutes. The coating, cleaning, autoclaving, and testing procedures were repeated according to Example 73.

Example 76: Extracted, dried and dip coated lenses. In other examples, the lenses were placed in 1.5 ml of IPA or MeOH (solvent) and placed on a mixing table for 12-18 hours. Swing the solvent and match the corresponding solvent The lenses were washed for an additional hour. The solvent was replaced with deionized water, and the lenses were rinsed 3 times for 30 minutes to 1 hour each. The lenses were dried in a vacuum chamber for 2-24 hours.

The lens surfaces were functionalized using nitrogen gas in a standard plasma chamber (Plasma etch PE-50) set at 200 mTorr, 3 min, 100 W RF power, 5-20 standard cubic meters per minute. Then use the lenses within 1 hour. The lenses were coated, cleaned, autoclaved and tested according to the aqueous procedure of Example 73.

Example 77: Lenses dipped and subjected to accelerated lifetime testing to confirm the stability of the bulk layer of PEG. In other instances, the steps of Example 73 were repeated for contact lenses (PureVision, Balafec A, and MJS Lens Technology Ltd). Following autoclaving and testing procedures, the lenses were placed in PBS and autoclaved one more time or placed in sterile saline. The lenses were placed in a compounding oven (Stovall Life Science Inc) at 20, 40 or 60°C. These series of tests correspond to the 6 to 12 month date of the accelerated use period as detailed in FDA 510K clearance requirements for medical devices in general (and in particular for daily wear contact lenses). After testing, the sterile saline was replaced with fresh sterile saline, and the lenses in the individual mixing ovens were replaced.

Example 78: Characterized coating via trapped bubble contact angle test. In other instances, to measure the contact angle, trapped bubble techniques are used. Lenses are mounted on small plates with spherical features. The lenses were immersed in PBS and suspended on top of a plate with holes through which the convex surfaces of the lenses protruded downward. Place a blunt needle just below the surface in the center of the lens. The bubble is then advanced using a syringe pump until it contacts the lens, at which point the bubble is withdrawn until it bursts out of the lens or needle. Through a magnifying lens, a high-definition camera records the complete process, and then stores the frame from the moment before the bubble escapes the lens or the needle. From the image, the angle between the lens and both sides of the bubble was calculated in MATLAB and stored as the contact angle of the lens.

Example 79: Lubricity Test Method

A test method was designed and established to observe the effect of the hydrogel coating on the lubricity of the lenses. Three contact lenses were used in this evaluation:

1. Packaging Polysilicon Hydrogel Lens A

2. Polysiloxane hydrogel lens A coated with hydrogel

3. Pack Silicone Hydrogel Lens B for 6 seconds

The borosilicate glass plate was cleaned and immersed in a PBS bath. One end of the board was shim raised 30mm to create a slope of ~11 degrees. A test lens was placed on top of this slope and weighted using stainless steel bolts, weighing approximately 1.13 grams. The lenses made it possible to slide down the slope ~152mm and record the time required to reach the bottom of the slope. result:

Test Results Illustrating the Lubricity Ratio of Hydrogel Coated Lenses Significant increases were seen in the uncoated control group.

As used herein in the specification and claims, including in the Examples, unless otherwise specified, all numbers are to be read as having the preface "about" or "approximately" even if not explicitly shown. The word "about" or "approximately" may be used when describing a value and/or location to mean that the stated value and/or location is within a reasonable expected range of the value and/or location. For example, a numerical value may have +/- 0.1% of the stated value (or range of values), +/- 1% of the stated value (or range of values), +/- 2% of the stated value (or range of values), +/- 5% of the stated value (or range of values), +/- 10% of the stated value (or range of values), etc. Any numerical range recited herein is intended to include all subranges subsumed therein.

As for other details related to the present invention, materials and manufacturing techniques within the level of those skilled in the relevant art may be employed. The same applies to the usual or logically used additional functions of the method-based aspects of the invention. Also, it is contemplated that any optional feature of the described variations of the invention may be set forth and claimed independently or in combination with one or more of the features described herein. Likewise, a singular item reference includes the possibility that there are multiples of the same item. More particularly, as used herein and within the scope of the claims, the singular forms "a (a, an)" and "said, the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the draft patent scope may exclude any arbitrary elements. As such, this statement is intended to serve as a basis for the foregoing to use exclusive terms such as "only," "only," or the use of a "negative" limitation in connection with the reference to the claimed element. Unless otherwise defined herein, all techniques and Academic terms have the same meanings commonly understood by those skilled in the art to which this invention pertains. The breadth of the invention is not limited by the subject description, but only by the ordinary meaning of the claimed terms used.

N1/N2: Reaction part

A: Reactive functional group

Claims (23)

A method of making a hydrogel-coated contact lens, comprising: reacting an outer surface of the contact lens with a first polymer species of a hydrophilic polymer solution, wherein the first polymer species comprises an electron pair acceptor an electron pair accepting moiety, and a first moiety of the electron pair accepting moiety forms a covalent attachment to the outer surface of the contact lens via a first nucleophilic conjugate reaction; and polymerizing the hydrophilic The first polymer species of the polymer solution is reacted with a second polymer species of the hydrophilic polymer solution, the second polymer species comprising a compound suitable for use with the first polymer species in a second nucleophilic conjugation reaction A second portion of the electron pair accepting moiety is covalently linked to at least partially cross-link the first polymer species and the nucleophilic reactive moiety of the second polymer species, wherein the hydrogel coating is formed and Covalently attached to the outer surface of the contact lens by the first and second nucleophilic conjugation reactions. The method of claim 1, further comprising modifying the outer surface of the contact lens to form a plurality of reactive nucleophilic sites on the outer surface. The method of claim 2, wherein the modifying step comprises exposing the outer surface of the contact lens to gas plasma treatment. Apply for the method in item 2 of the scope of the patent, wherein the invisible Reacting the outer surface of the lens with the first polymer species includes reacting at least a portion of the plurality of reactive nucleophilic sites on the outer surface with a first portion of the electron pair accepting moiety on the first polymer species. The method of claim 1 of the claimed scope, wherein the first and second nucleophilic conjugation reactions are both 1,4-nucleophilic addition reactions. The method of claim 1 of the claimed scope, wherein the first and second nucleophilic conjugation reactions are both Michael-type reactions. The method of claim 1 of the claimed scope, wherein the first and second nucleophilic conjugation reactions are both click reactions. The method of claim 1 of the claimed scope, wherein the nucleophilic reactive moiety of the second polymer species is an amine group, and the electron pair accepting moiety of the first polymer species is a thiol group. The method of claim 1, wherein the first polymer species and the second polymer species are cross-linked via a sulfonamide moiety. The method of claim 1, wherein the hydrophilic polymer solution comprises substantially equal concentrations of the first polymer species and the second polymer species. The method of claim 1, wherein the concentration of electron pair accepting moieties of the first polymer species is 1% to 30% higher than the concentration of nucleophilic reactive moieties of the second polymer species. For the method of claim 1 of the scope of the patent application, wherein the first polymer The concentration of electron pair accepting moieties of the compound species is 5% to 20% higher than the concentration of nucleophilic reactive moieties of the second polymer species. The method of claim 1, wherein the reaction steps are carried out at a temperature between 15°C and 100°C. The method of claim 1, wherein the reaction steps are carried out at a temperature between 20°C and 40°C. The method of claim 1, wherein the reaction steps are carried out at a pH between 7 and 11. The method of claim 1, wherein the hydrogel coating is substantially optically transparent. The method of claim 1 of the claimed scope, wherein the contact lens comprises a core composed of polysiloxane. The method of claim 1, wherein the contact lens includes a core comprising polysiloxane. The method of claim 1, wherein the contact lens includes a core that is substantially free of polysiloxane. The method of claim 19, wherein the contact lens includes a hydrogel core. The method of claim 1 of the claimed scope, wherein the second polymer species is polyethylene glycol or polyacrylamide. The method of claim 1 of the claimed scope, wherein the first polymer species is polyethylene glycol or polyacrylamide. The method of claim 1, wherein the hydrogel layer comprises a thickness between 0.01 microns and 0.05 microns.

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